Update v1.1

Based on the FDA approvals for pembrolizumab for patients with recurrent or metastatic cutaneous squamous cell carcinoma [Ref 108, 169] and toripalimab in combination with cisplatin and gemcitabine for first-line treatment of patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma, or as a monotherapy for treatment of adult patients with recurrent, unresectable, or metastatic nasopharyngeal carcinoma with disease progression on or after platinum-containing chemotherapy [Ref 170, 171], the guideline has been updated.

The following recommendations were added or amended:

• Cemiplimab or pembrolizumab, if not contraindicated (eg, organ transplant recipients), should be prescribed for patients with metastatic or locally-advanced cSCC in the head and neck region who are not candidates for curative surgery or radiation, or for whom neoadjuvant response reduces the morbidity of definitive therapy.

• For patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma, first-line treatment with toripalimab in combination with cisplatin and gemcitabine is recommended.

  • There is clinical evidence for other PD-1 inhibitors as well, and these may be substituted if toripalimab is unavailable.

• For patients with recurrent unresectable or metastatic nasopharyngeal carcinoma who have disease progression on or after platinum-containing chemotherapy, toripalimab monotherapy is recommended.

  • There is clinical evidence for other PD-1 inhibitors as well, and these may be substituted if toripalimab is unavailable.

Update v1.1

Based on the practice changing data reported in CheckMate 141 regarding nivolumab as a first-line treatment in R/M HNSCC after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (ie, with radiation) setting [Ref 172], and the practice-changing data reported from the KEYNOTE-B10 and FRAIL-IMMUNE/GORTEC 2018-03 trials regarding anti-PD-1 ICIs in combination with carboplatin + paclitaxel for patients with treatment-naïve R/M HNSCC who are frail and/or not eligible for cisplatin-based therapies [Refs 173, 174], the guideline has been updated.

The following recommendations have been added or revised for 'First-line treatment with PD-1 inhibitors'

Pembrolizumab is indicated for treatment-naïve R/M HNSCC. * Pembrolizumab monotherapy may be used to treat patients with treatment-naïve R/M HNSCC and PD-L1 CPS ≥1. * Pembrolizumab + chemotherapy may be used to treat all patients with treatment-naïve R/M HNSCC. Use of chemotherapy is particularly considered in patients who are symptomatic given the higher ORR for combination pembrolizumab plus chemotherapy. Treatment options include: - Pembrolizumab + chemotherapy (platinum and 5-FU). - If preferred, pembrolizumab plus carboplatin plus paclitaxel may be used as first-line treatment in patients with R/M HNSCC based on the initial results of the phase IV, single-arm, open-label KEYNOTE-B10 study. The GORTEC 2018-03 study supports the combination of weekly carboplatin and paclitaxel with immunotherapy for older patients and those with co-morbidity.

For biomarker-unspecified patients with R/M HNSCC whose disease has progressed within 6 months of platinum-based chemoradiotherapy, pembrolizumab or nivolumab monotherapy may be used.

The following recommendations have been added or revised for 'Second-line treatment with PD-1 inhibitors'

For patients with R/M HNSCC who are platinum-refractory and immunotherapy-naive:

• Pembrolizumab or nivolumab monotherapy should be used.
• If a clinical trial is available, this is the preferred option.

For R/M HNSCC patients with disease progression following ICI monotherapy, clinical trial enrollment or guideline-based standard of care is recommended.

For R/M HNSCC patients with disease progression on or after systemic platinum-based chemotherapy in combination with ICI therapy, clinical trial enrollment or guideline-based standard of care is recommended.

Last Reviewed 11/15/2024 (v1.1 Update)

SITC continuously evaluates the field for practice-changing data and new FDA approvals. The information on this page provides a detailed overview of updates to the guideline content based on changes in the field. Updates to the guideline outlined below were made with the approval of SITC's Head and Neck Squamous Cell Carcinoma (HNSCC) Guideline Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

Update v1.1 Summary * The FDA approved pembrolizumab for patients with recurrent or metastatic cutaneous squamous cell carcinoma in June 2020 [Ref 108, 169].

• The FDA approved toripalimab in combination with cisplatin and gemcitabine for first-line treatment of patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma, or as a monotherapy for treatment of adult patients with recurrent, unresectable, or metastatic nasopharyngeal carcinoma with disease progression on or after platinum-containing chemotherapy in October 2023 [Ref 170, 171].

• Practice-changing data have been reported from CheckMate 141 regarding nivolumab as a first-line treatment in recurrent or metastatic HNSCC after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (ie, with radiation) setting [Ref 172].

• Practice-changing data have been reported from KEYNOTE B10 and the FRAIL-IMMUNE/GORTEC 2018-03 trials, demonstrating efficacy of combining an anti-PD-(L)1 immune checkpoint inhibitor (ICI) with carboplatin + paclitaxel in frail patients with R/M HNSCC [Ref 173, 174].

Update v1.1

The following references have been added:

1. FDA approves pembrolizumab for cutaneous squamous cell carcinoma. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-cutaneous-squamous-cell-carcinoma

2. FDA approves toripalimab-tpzi for nasopharyngeal carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-toripalimab-tpzi-nasopharyngeal-carcinoma

3. Food and Drug Administration, Coherus BioSciences. LOQTORZ (toripalimab-tpzi) prescribing information. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761240 Accessed 6/27/24.

4. Gillison ML, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington KJ, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Li L, Ferris RL. CheckMate 141: 1‐Year Update and Subgroup Analysis of Nivolumab as First‐Line Therapy in Patients with Recurrent/Metastatic Head and Neck Cancer. The Oncologist, 2018 Sept. https://doi.org/10.1634%2Ftheoncologist.2017-0674"10.1634/theoncologist.2017-0674

5. Dzienis MR, Cundom JE, Fuentes CS, Hansen AR, Nordlinger MJ, Pastor AV, Oppelt P, Neki A, Gregg RW, Lima IPF, Franke FA, daCunha Junior GF, Tsent JE, Loree T, Joshi AJ, Mccarthy JS, Naicker N, Sidi Y, Gumuscu B, De Castro Jr G. 651O Pembrolizumab (pembro) + carboplatin (carbo) + paclitaxel (pacli) as first-line (1L) therapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Phase VI KEYNOTE-B10 study. Annals of Oncology, 2022 Sept. https://doi.org/10.1016/j.annonc.2022.07.775

6. Fayette J, Cropet C, Gautier J, Toullec C , Burgy M, Bruyas A, Sire C, Lagrange A, Clatot F, Calderon B, Vinches M, Iacob M, Martin L, Neidhardt Berard EM, Kaminsky MC, Vansteene D, Salas S, Champagnac A, Pérol D, Bourhis J. Results of the multicenter phase II FRAIL-IMMUNE trial evaluating the efficacy and safety of durvalumab combined with weekly paclitaxel carboplatin in first-line in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) not eligible for cisplatin-based therapies. J Clin Oncol 41, 2023 (suppl 16; abstr 6003).

Figure 2 has been updated. See updated Figure 2.

Update v1.1

Figure 1 has been updated to incorporate FDA-approvals and practice-changing data. See updated Figure 1. [Ref 108, 169, 171-174]

Update v1.1

Some recommendations in Table 1 have been updated to include FDA approvals and practice-changing data that have been reported since publication of this guideline. The updated recommendations can be found in the text overlays and in the updated Table 1 [Ref 108, 169-174].

This supplement is part 2 of 2 supplements published in conjunction with the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting. For access to the other supplement, see below.

SITC 39th Annual Meeting (SITC 2024) Abstracts https://jitc.bmj.com/content/12/Suppl_2

This supplement is part 1 of 2 supplements published in conjunction with the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting. For access to the second supplement, see below.

SITC 39th Annual Meeting (SITC 2024) Late Breaking Abstracts https://jitc.bmj.com/content/12/Suppl_3

v3.2 Update

The following references have been added:

1. Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, et al. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. New England Journal of Medicine. 2024. doi: https://doi.org/10.1056/nejmoa2402604

2. Food and Drug Administration (FDA) IB. Lifileucel (AMTAGVI) prescribing information. n.d. Available: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/amtagvi

3. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. Journal for ImmunoTherapy of Cancer. 2022;10:e005755. https://doi.org/10.1136/jitc-2022-005755

4. Grigoleit G-U, Kluger H, Thomas S et al. 1086MO Lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced mucosal melanoma after progression on immune checkpoint inhibitors (ICI): Results from the phase II C-144-01 study. Annals of Oncology. doi:https://doi.org/10.1016/j.annonc.2023.09.2220

5. Food and Drug Administration (FDA) BMS. Nivolumab (OPDIVO) prescribing information. n.d. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125554

v3.2 Update

New recommendation:

• For patients with metastatic mucosal melanoma, early use of lifileucel (LE:3) or another adoptive cell therapy should be considered.

v3.2 Update

Revised recommendation:

• For all patients with advanced melanoma whose disease has progressed on anti-PD-1 therapy and clinical trial enrollment is not feasible, dual ICI therapy, adoptive cell therapy with lifileucel (LE:3), or BRAF-targeted therapy (if appropriate) should be considered, with choice of therapy taking anticipated toxicities and phenotype of resistance (primary versus secondary) into account.
  • For patients whose best response is PD or <6 months of SD following at least 6 weeks of therapy with a single anti-PD-1 agent (ie, primary anti-PD-1 ICI resistance), combination ipilimumab plus nivolumab (LE:2) or treatment with lifileucel (LE:3) is preferred and ipilimumab monotherapy (LE:2) or ipilimumab plus pembrolizumab (LE:3) can be considered.
  • For patients who initially benefited from anti-PD-1-based monotherapy for at least 6 months, discontinued therapy, and then ultimately progressed, re-induction with single-agent anti-PD-1 can be considered on progression of disease (LE:3).

v3.2 Update

Revised recommendation:

• For all patients with advanced melanoma whose disease has progressed on any anti-PD-1-based ICI therapy without an anti-CTLA-4 agent, there is no clear standard of care subsequent line therapy and thus treatment with ipilimumab plus nivolumab (LE:2), BRAF-targeted agents (if appropriate) if not already done (LE:2), lifileucel (LE:3), or enrollment in clinical trials evaluating strategies including adoptive cell therapies, novel combinations, and other strategies, should be strongly encouraged in shared decision-making with the patient.

v3.2 Update

New recommendation:

• For patients being considered for treatment with lifileucel, consultation with or referral to a treatment center with experience in administering cell therapies is recommended.

v3.2 Update

New recommendation:

• For patients with brain metastases that are treated and stable, referral for lifileucel can be considered. Patients with active brain metastases are ineligible for lifileucel/TIL therapy, unless done as part of a clinical trial.

v3.2 Update

Revised recommendation:

• For patients with resectable stage IIIB to IV (without brain metastases) melanoma, while there were no approved neoadjuvant therapies at the time of manuscript publication, neoadjuvant pembrolizumab continued into the adjuvant setting demonstrated improved EFS compared with adjuvant therapy alone in a randomized, phase II trial (LE:2). Neoadjuvant ipilimumab with nivolumab with subsequent adjuvant therapy determined by pathologic analysis demonstrated improved EFS compared to adjuvant therapy alone in a randomized phase III trial (LE:2). Neoadjuvant approaches should be considered after multidisciplinary discussion for patients with high-risk stage III and resectable stage IV melanoma. Consideration for clinical trial enrollment is still preferred for eligible patients with high-risk stage III disease.

Last Reviewed 9/20/2024 (v3.2 Update)

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Melanoma Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

v3.2 Update Summary

An addendum to the SITC Melanoma v3.0 CPG is currently in preparation to address practice-changing data and approvals since publication of the guideline.

As part of the forthcoming addendum, the SITC Melanoma CPG Expert Panel has updated the recommendations in this guideline to address the following:

• Practice-changing data demonstrating the efficacy of neoadjuvant nivolumab and ipilimumab followed by surgery in patients with resectable stage III melanoma were reported from the NADINA trial (NCT04949113) in June 2024 [Ref 275].

• The FDA granted accelerated approval to lifileucel (autologous tumor-infiltrating lymphocyte therapy) for adult patients with unresectable or metastastic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 positive a BRAF inhibitor with or without a MEK inhibitor in February 2024 [Ref 276-278].

• The FDA approved nivolumab for the adjuvant treatment of completely resected stage IIB/C melanoma in patients 12 years and older in October 2023 [Ref 279]

v2.4 Update

Table 5 - mUC treatment algorithm has been updated based on the FDA approvals for enfortumumab vedotin + pembrolizumab and for nivolumab in combination with gemcitabine and cisplatin for patients with advanced mUC. See here for revised Table 5 - mUC treatment algorithm [Ref 3, 6, 158].

v2.3 Update

Table 5 - mUC treatment algorithm has been updated based on the label change for pembrolizumab, the voluntary withdrawal of the atezolizumab indication, and the approval of pembrolizumab plus enfortumab vedotin for the treatment of patients with advanced mUC [Ref 3, 158, 161].

v2.4 Update

New Panel recommendation:

• Based on the data demonstrating that FGFR3 mutations are not associated with resistance to PD-(L)1 blockade, patients with metastatic FGFR3-mutant urothelial cancer should not be precluded from receiving anti-PD-(L)1 therapy prior to erdafitinib (LE:2).

v2.3 Update

In August 2021, the indication for pembrolizumab for the treatment of patients with metastatic or locally advanced mUC ineligible for platinum-containing chemotherapy or with disease progression on or after platinum-containing chemotherapy was converted to full approval and revised to no longer specify PD-L1 expression status for eligibility [Ref 3].

In November 2022, the confirmatory trial for the atezolizumab accelerated approval, IMvigor130, did not meet the co-primary endpoint of OS for atezolizumab plus chemotherapy versus chemotherapy alone, and the indication for atezolizumab for the treatment of patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1–stained tumor-infiltrating immune cells covering ≥5% of the tumor area) or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status was voluntarily withdrawn by the manufacturer [Ref 161].

The FDA granted an accelerated approval for pembrolizumab plus enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy in April 2023. Approval was based on ORR and DOR data from the phase II, multi-cohort EV-103/KEYNOTE-869 (NCT03288545) trial, which enrolled patients that had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. ORR (n = 121) was 68% (95% CI 59% to 76%), DOR for Cohort K (patients randomized to receive either the combination or enfortumab vedotin alone) was NR (range 1 to 24+ months), and DOR for the dose escalation Cohort plus Cohort A (all patients received enfortumab vedotin plus pembrolizumab) was 22 months (range 1+ to 46+). Enfortumab vedotin is also approved as a single agent for patients with locally advanced or metastatic mUC who have previously received an anti-PD-(L)1 ICI and platinum-contain chemotherapy, or who are cisplatin-ineligible and have received one or more prior lines of therapy [Ref 3, 158].

v2.4 Update

Table 2 - NMIBC Immunotherapy treatment algorithm has been updated based on the approval of nogapendekin alfa inbakicept in combination with BCG for the treatment of BCG-unresponsive NMIBC with CIS with or without papillary tumors. See here for revised Table 2 - NMIBC immunotherapy treatment algorithm [Ref 160].

v2.3 Update

Table 2 - NMIBC Immunotherapy treatment algorithm has been updated to include nadofaragene firadenovec as a treatment option for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors [Ref 162].

v2.4 Update

In cohort 2 of the randomized phase 2 THOR study (NCT03390504), erdafitinib versus pembrolizumab had similar median overall survival in an anti–PD-(L)1-naive, FGFR-altered population of patients with metastatic urothelial cancer who had progressed despite prior platinum-based chemotherapy [Ref 159]. These results reinforce that FGFR3 mutations are not associated with resistance to PD-(L)1 blockade and that patients with metastatic FGFR3 mutant urothelial cancer should generally receive anti-PD-(L)1 therapy prior to erdafitinib.

v2.3 Update

In August 2021, the indication for pembrolizumab for the treatment of patients with metastatic or locally advanced mUC ineligible for platinum-containing chemotherapy or with disease progression on or after platinum-containing chemotherapy was converted to full approval and revised to no longer specify PD-L1 expression status for eligibility [Ref 3].

In November 2022, the indication for atezolizumab for the treatment of patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1–stained tumor-infiltrating immune cells covering ≥5% of the tumor area) or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status was voluntarily withdrawn by the manufacturer [Ref 161].

v2.4 Update

The following references have been added:

1. Food and Drug Administration (FDA) AP. Enfortumab vedotin (PADVEC) prescribing information. n.d. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761137

2. Siefker-Radtke A, Matsubara N, Park S, Huddart R, Burgess E, Özgüroğlu M, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Annals of Oncology. 2024;35(1):107-17. https://doi.org/10.1016/j.annonc.2023.10.003

3. Food and Drug Administration (FDA) AB. Nogapendekin alfa-inbakicept (ANKTIVA) prescribing information. n.d. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761336

4. Genentech Provides Update on Tecentriq U.S. Indication for Previously Untreated Metastatic Bladder Cancer. Available: https://www.gene.com/media/statements/ps_112822 Accessed: 9/18/24

5. Food and Drug Administration (FDA) FP. Nadofaragene firadenovec (ADSTILADRIN) prescribing information. n.d. Available: https://www.fda.gov/media/164029/download

6. Chamie K, Chang SS, Kramolowsky E, Gonzalgo ML, Agarwal PK, Bassett JC, et al. IL-15 superagonist NAI in BCG-unresponsive non–muscle-invasive bladder cancer. NEJM evidence. 2022;2(1):EVIDoa2200167. https://doi.org/10.1056/evidoa2200167

7. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. New England Journal of Medicine. 2024;390(10):875-88. https://doi.org/10.1056/nejmoa2312117

8. Van Der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, et al. Nivolumab plus gemcitabine–cisplatin in advanced urothelial carcinoma. New England Journal of Medicine. 2023;389(19):1778-89. https://doi.org/10.1056/nejmoa2309863

Data in this table are as of the time of guideline publication.

v2.4 Update

EV302 (NCT04223856) met its primary end-points, and in December 2023, the FDA approved EV in combination with pembrolizumab for first-line treatment of advanced or mUC [Ref 164].

v2.4 Update

Revised Panel recommendation:

• Pembrolizumab is recommended for the treatment of patients with platinum-refractory mUC who have not received prior ICI treatment based on a significant OS benefit in a randomized phase III trial (LE: 2). Avelumab and nivolumab also have approvals in this setting (LE:3).

v2.4 Update

Revised Panel recommendation:

• For patients with mUC, first-line treatment options include enfortumab vedotin plus pembrolizumab (preferred) regardless of whether patients are cisplatin-eligible or cisplatin-ineligible (LE:2), or gemcitabine, cisplatin, plus nivolumab in patients who are cisplatin-eligible (LE:2). Both of these regimens have been shown to improve OS compared with platinum-based chemotherapy alone.

v2.1 Update

Full approval of nivolumab in this setting was granted in August, 2021 [Ref 6].

v2.3 Update

In November 2022, the confirmatory trial for the atezolizumab accelerated approval, IMvigor130, did not meet the co-primary endpoint of OS and the indication for atezolizumab for first-line treatment of PD-L1-positive mUC in patients who are ineligible for cisplatin-containing chemotherapy or those who are not eligible for any platinum-based chemotherapy, regardless of PD-L1 status, was voluntarily withdrawn by the manufacturer [Ref 161].

Data in this table are as of the time of guideline publication.

v2.2 Update

In August 2021, the indication for pembrolizumab for the treatment of patients with metastatic or locally advanced mUC ineligible for platinum-containing chemotherapy or with disease progression on or after platinum-containing chemotherapy was converted to full approval and revised to no longer specify PD-L1 expression status for eligibility [Ref 3].

v2.3 Update

In November 2022, the confirmatory trial for the atezolizumab accelerated approval, IMvigor130, did not meet the co-primary endpoint of OS and the indication for atezolizumab for first-line treatment of PD-L1-positive mUC in patients who are ineligible for cisplatin-containing chemotherapy or those who are not eligible for any platinum-based chemotherapy, regardless of PD-L1 status, was voluntarily withdrawn by the manufacturer [Ref 161].

v2.4 Update

In addition to the FDA approved first-line treatment regimens mentioned in this section, enfortumab vedotin plus pembrolizumab received accelerated FDA approval in December, 2023 for the treatment of advanced or mUC based on the efficacy data from the phase III EV302 trial (NCT04223856). The median PFS was 12.5 months (95% CI 10.4 to 16.6) for the EV plus pembrolizumab arm (n=442) and 6.3 months (95% CI 6.2 to 6.5) for the chemotherapy group (n=444) (HR = 0.45; p < 0.001). The median OS was also improved in the EV plus pembrolizumab treatment relative to the chemotherapy arm at 31.5 months (95% CI 25.4 to NE) and 16.1 months (95% CI 13.9 to 18.3) respectively (HR = 0.47; p < 0.001). Grade ≥3 treatment related adverse events occurred in 55.9% of patients in the EV plus pembrolizumab group and in 69.5% of patients receiving chemotherapy. [Ref 3, 158, 164].

The FDA also approved nivolumab in combination with gemcitabine and cisplatin for the first-line treatment of patients with unresectable or metastatic UC in March, 2024. This approval was based on efficacy data evaluated in the CheckMate-901 trial. The median OS was longer in patients receiving nivolumab in combination with cisplatin and gemcitabine followed by nivolumab alone (n=304) relative to patients receiving gemcitabine-cisplatin alone (n=304), at 21.7 months (95% CI 18.6 to 26.4) and 18.9 months (95% CI 14.7 to 22.4) respectively (HR = 0.78; p = 0.02). The median PFS was also improved in the patients receiving the nivolumab combination therapy in comparison to gemcitabine-cisplatin treatment, at 7.9 months (95% CI 7.6 to 9.5) and 7.6 months (95% CI 6.1 to 7.8) respectively (HR = 0.72; p = 0.001). Grade ≥3 treatment related adverse events occurred in 61.8% of patients receiving the nivolumab combination treatment and in 51.7% of patients in the gemcitabine-cisplatin group [Ref 6, 165].

v2.4 Update

Since the approvals of enfortumab vedotin + pembrolizumab and nivolumab + cisplatin + gemcitabine for the treatment of advanced mUC, these treatment combinations have become first-line SOC.

v2.1 Update

Recommendation modified to include information on the approval of nivolumab as adjuvant treatment for patients with surgically resected, high-risk MIBC, as noted below:

• For patients with MIBC at high risk for recurrence after radical resection (ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin-based chemotherapy or pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin-based chemotherapy and who also either were ineligible for or refused adjuvant cisplatin-based chemotherapy) adjuvant nivolumab extends DFS as demonstrated in CheckMate 274 (LE: 2). Neoadjuvant therapy with cisplatin-based combination chemotherapy remains the treatment paradigm for curative intent therapy when surgery is considered; the data of CheckMate 274 are insufficient to conclude that adjuvant immunotherapy alone can replace the current practice which is known to maximize survival. Active investigation is ongoing into various additional neoadjuvant and/or adjuvant strategies (and bladder preservation), either as single agents, or in combination with chemotherapy, radiotherapy, or novel agents.

v2.1 Update

Since guideline publication, the FDA approved nivolumab for the adjuvant treatment of patients with urothelial cancer (UC) who are at high risk of recurrence after undergoing radical resection in August 2021 [Ref 6].

v2.3 Update

In December 2022, the FDA approved nadofaragene firadenovec, a non-replicating (cannot multiply in human cells) adenoviral vector based gene therapy indicated for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors [Ref 162].

Approval was based on results from Study CS-003 (NCT02773849), a single-arm study that enrolled 157 patients who had high-risk NMIBC, 98 of whom had BCG-unresponsive disease. The registrational data leading to approval reported a CR rate of 51% (95% CI 41% to 61%) in patients that recieved nadofaragene firadenovec (CR defined as the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine). The median DOR was 9.7 months (range 3 to 52+), and 46% remained in CR for at least 1 year [Ref 162].

v2.4 Update

Revised recommendation: * The following treatments are approved for adult patients with Bacillus Calmette Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors: pembrolizumab monotherapy (LE:2), nadofaragene firadenovec-vcng monotherapy (LE:2), or nogapendekin alfa inbakicept-pmln in combination with BCG. The decision as to which of these agents should be used should be based on shared decision making, taking into account factors such as efficacy, adverse events and also patient preferences regarding scheduling and administration routes.

v2.4 Update

Nogapendekin alfa-inbakicept (NAI), an interleukin 15 (IL-15) superagonist, gained FDA approval in April, 2024 as a combination treatment with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. Approval was based on complete response data from QUILT-3.032 (NCT0302285), a single-arm, multicenter trial that enrolled 77 patients (cohort A) with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors to receive NAI in combination with BCG. Complete response at any time (assessed every 3 months for up to 2 years) was reported in 62% (95% CI 51% to 73%) of patients, with 58% of complete responders having a DOR ≥ 12 months and 40% of complete responders having a DOR ≥ 24 months. Serious adverse reactions occurred in 16% of patients, with the most common adverse reaction being hematuria (3.4%) [Ref 160, 163].

v2.3 Update

In December 2022, the FDA approved nadofaragene firadenovec, a non-replicating (cannot multiply in human cells) adenoviral vector based gene therapy indicated for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. [Ref 162].

v2.3 Update Revised recommendation:

• PD-L1 expression by IHC should not be used to guide first-line therapy in patients with mUC.

Last Reviewed 10/19/2024 (v2.4 Update)

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Urothelial Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

v2.4 Update Summary

• The FDA granted accelerated approval of enfortumab vedotin in combination with pembrolizumab for the treatment of adult patients with locally advanced or metastatic urothelial cancer in December 2023 [Ref 3, 158].

• The FDA granted approval of nivolumab in combination with cisplatin and gemcitabine as first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma in March 2024 [Ref 6].

• Data have been reported indicating similar responses to ICI therapy regardless of FGFR3 mutation status for patients with metastatic urothelial cancer [Ref 159].

• The FDA granted approval of nogapendekin alfa inbakicept with BCG for adult patients with BCG-unreseponsive NMIBC with carcinoma in situ with or without papillary tumors in April 2024 [Ref 160].

v2.3 Update Summary

• Atezoluzimab for the treatment of cisplatin- and platinum-ineligible patients with mUC was voluntary withdrawn by the manufacturer in November, 2022 [Ref 161].

• The FDA granted approval of nadofaragene firadenovec for the treatment of BCG-unresponsive NMIBC with CIS with or without papillary tumors in December 2022 [Ref 162].

• The FDA granted accelerated approval of enfortumab vedotin with pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy in April 2023 [Ref 3, 158].

v2.2 Update Summary * The indication of pembrolizumab for the treatment of patients with mUC ineligible for platinum-containing chemotherapy or with disease progression on or after platinum-containing chemotherapy was revised in August 2021 to no longer specify PD-L1 status for eligibility [Ref 3].

v2.1 Update Summary * The FDA granted approval of nivolumab for the treatment of patients with urothelial cancer who are at high risk of recurrence after undergoing radical resection in August 2021 [Ref 6].

See the highlighted text for updated content and more detailed information.

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Gastrointestinal Cancer CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

v1.1 Update Summary

An update to the SITC Gastrointestinal Cancer CPG is currently in preparation to address practice-changing data and new FDA approvals for ICI-based treatments of biliary tract cancer, gastric or gastroesophageal junction adenocarcinoma, and esophageal squamous cell carcinoma.

This article is part of the special JITC series: The Next Wave of Immuno-oncology: A Roadmap from the Society for Immunotherapy of Cancer (SITC)

This article is part of the special JITC series: SITC 40th Anniversary: I-O Progress and Potential

This article is part of the special JITC series: Computational Immuno-Oncology

This article is part of the special JITC series: Cancer Immunotherapy in Understudied Populations

This article is part of the special JITC series: Cancer Immunotherapy in Understudied Populations

This article is part of the special JITC series: Cancer Immunotherapy in Understudied Populations

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Lymphoma Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines

An update to the SITC Lymphoma CPG is currently in preparation to address practice-changing data and new FDA approvals of immune checkpoint inhibitors, CAR T cell therapies, antibody-drug conjugates, monoclonal antibodies, bispecific T cell engagers, immunomodulatory agents, and a cytotoxic recombinant protein. These approvals and practice-changing data will affect the recommendations across a variety of disease states within this guideline.

Update 10-22-2022

Based on the approval of axicabtagene ciloleucel for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy, the Lymphoma CPG has been updated in the following locations: * Available Agents and Indications for NHL * Expert Panel Recommendations for NHL * Expert Panel Recommendations for NHL

Reference: Axicabtagene ciloleucel (YESCARTA) FDA press release

Based on the approval of tisagenlecleucel for the treatment of adult patients with relapsed or refractory follicular lymphoma following 2 or more lines of systemic therapy, the Lymphoma CPG has been updated in the following location: * Available Agents and Indications for NHL

Reference: Tisagenlecleucel (KYMRIAH) FDA press release

Based on the approval of lisocabtagene maraleucel for the treatment of adult patients with large B-cell lymphoma (LBCL) who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age, the Lymphoma CPG has been updated in the following location: * Available Agents and Indications for NHL

Reference: Lisocabtagene maraleucel (BREYANZI) FDA press release

Update 6-3-2021

Based on the approval of loncastuximab tesirine-lpyl for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma, the Lymphoma CPG has been updated in the following location: * Available Agents and Indications for NHL

Reference: Loncastuximab tesirine-lpyl (ZYNLONTA) FDA press release

Update 2-9-2021

The Lymphoma CPG has been updated in the following location: * Immunotherapies in Development for NHL * Expert Panel Recommendations for NHL

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Lung Cancer and Mesothelioma Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

v2.1(A) Update Summary

An addendum to the SITC Lung Cancer and Mesothelioma CPG is currently in preparation to address new FDA approvals and practice-changing data for the treatment of metastatic or locally advanced NSCLC, resectable NSCLC, LS-SCLC, and malignant pleural mesothelioma using ICI-based treatment regimens. This update in preparation will also address the FDA approval of the bispecific antibody, tarlatamab, for the treatment of ES-SCLC.

Last reviewed 12/14/2023 (v1.1 Update)

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication and made with the approval of the SITC NMSC CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

v1.1 Update Summary

• The FDA granted accelerated approval for retifanlimab (anti-PD-1 ICI) for the treatment of adult patients with metastatic or recurrent locally advanced MCC in March 2023. The NMSC CPG was updated in the following locations: Introduction, Merkel Cell Carcinoma, Recommended Immunotherapies for MCC, Figure 1 – FDA-Approved ICI agents for NMSC, Table 2 – NMSC Landmark Clinical Trial Data Leading to FDA Approvals for ICIs for MCC and Novel Strategies and Promising Future Directions. [Ref 177, 178]

• Data have been reported demonstrating efficacy with neoadjuvant anti-PD-1 ICI therapy prior to curative-intent surgery in patients with CSCC. Based on these practice-changing data, the NMSC CPG was updated in the following locations: Based on these practice-changing data, the NMSC CPG was updated in the following locations: Recommended Immunotherapies for CSCC, and Novel Strategies and Promising Future Directions for CSCC. [Ref 179]

• Data have been reported demonstrating efficacy combining an anti-PD-(L)1 ICI with an anti-CTLA-4 ICI for patients with advanced MCC. Based on these practice-changing data, the NMSC CPG was updated in the following locations: Merkel Cell Carcinoma, Recommended Immunotherapies for MCC, and Novel Strategies and Future Directions for CSCC. [Ref 180, 181]

See highlighted text for updated content and more detailed information.

As supplementary material to Addendum 1 (update v1.1(A)), SITC has created a treatment algorithm for HCC.

Last reviewed 6/16/23 (v1.1(A) update supplement)

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC HCC CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

SITC published an addendum to the guideline (Addendum 1, update v1.1(A)) based on the approval of tremelimumab in combination with durvalumab for adult patients with unresectable HCC. A supplementary immunotherapy treatment algorithm for HCC was generated based on the Expert Panel recommendations. It can be found on the SITC website here.

View the supplement to this addendum "HCC Immunotherapy Treatment Algorithm" on the SITC website.

Last reviewed 6/16/23 (v1.1(A) update supplement)

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC HCC CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

A supplementary immunotherapy treatment algorithm for HCC was generated based on the Expert Panel recommendations. It can be found on the SITC website here.

Update v1.1

New Recommendation: * For patients with FIGO 2014 stage III-IVA cervical cancer, pembrolizumab plus chemoradiotherapy is recommended.

Update v1.1

Table 2 has been revised to include trial data from KEYNOTE-A18 (NCT04221945) that led to the approval of pembrolizumab plus chemoradiotherapy for patients with FIGO stage III-IVA cervical cancer. Updated Table 2 can be found here.

Last Reviewed 5/25/24 (v1.1 Update)

SITC continuously evaluates the field for practice-changing data and new FDA approvals. The information on this page provides a detailed overview of updates to the guideline content based on changes in the field. Updates to the guideline outlined below were made with the approval of SITC's Gynecology Cancer CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

v1.1 Update Summary

• The FDA granted approval of pembrolizumab with chemoradiotherapy FIGO 2014 Stage III-IVA cervical cancer on January 12, 2024. Based on this approval, the Gynecologic Cancer CPG has been updated in the following location: Immunotherapy for the treatment of cervical cancer - Recommended immunotherapy treatments for cervical cancer (including Table 2). [Ref 13, 299, 300]

• The FDA granted approval of dostarlimab with carboplatin and paclitaxel, followed by single-agent dostarlimab for dMMR or MSI-H (as determined by an FDA-approved test) primary advanced or recurrent endometrial cancer on July 31, 2023. Based on this approval, the Gynecologic Cancer CPG has been updated in the following location: Immunotherapy for the treatment of endometrial cancer - Recommended immunotherapy treatments for endometrial cancer (including Table 3). [Ref 15, 121, 301]

See highlighted text for updated content and more detailed information.

Update v1.1

In addition to the approved ICI-based regimens described in this section, since guideline publication pembrolizumab with chemoradiotherapy was granted FDA approval for patients with FIGO 2014 stage III-IVA cervical cancer on January 12, 2024. Approval was based on the KEYNOTE-A18 (NCT04221945) trial. The primary outcome measures for approval were PFS and OS. Grade ≥ 3 TRAEs and any-grade irAEs occurred in 67% and 32% of patients in the pembrolizumab group, respectively. More information on the trial details can be found in the updated Table 2. [Ref 13, 299, 300]

Update v1.1

The following references have been added:

1. US Food and Drug Administration. FDA grants approval for pembrolizumab with chemoradiotherapy (CRT) for patients with FIGO 2014 Stage III-IVA cervical cancer on 2024 January 12. Accessed 5/24/24.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer

2. Lorusso D, Xiang Y, Hasagawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. The Lancet. 2024;403: 1341-1350.

3. US Food and Drug Administration. FDA grants approval for Dostarlimab (Jemperli, GlaxoSmithKline) + chemo for dMMR endometrial cancer. 2023 July 31. Accessed 5/24/24. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dostarlimab-gxly-chemotherapy-endometrial-cancer

Update v1.1

Revised Recommendation: * For first-line treatment of recurrent or metastatic endometrial cancer, carboplatin plus paclitaxel with or without trastuzumab (if HER2+ serous endometrial cancer) was the standard of care at the time of guideline publication (LE:2). Anti-PD-1 ICIs in combination with carboplatin plus paclitaxel demonstrated statistically significant and clinically meaningful improvements in PFS over chemotherapy alone for the treatment of previously untreated stage III or IV or first recurrent (after prior neoadjuvant or adjuvant chemotherapy) endometrial cancer. The observed benefit was regardless of MMR status (LE:2).

**Update v1.1 **

Table 3 has been revised to include trial data from RUBY (NCT03981796) that led to the approval of dostarlimab plus carboplatin and paclitaxel for patients with dMMR or MSI-H primary advanced or recurrent endometrial cancer. Updated Table 3 can be found here.

Update v1.1

Since guideline publication, dostarlimab with carboplatin and paclitaxel was FDA-approved for treatment of dMMR or MSI-H (as determined by an FDA-approved test) primary advanced or recurrent endometrial cancer on July 31, 2023. Approval was based on the RUBY (NCT03981796) trial, where the primary outcome measure was PFS. Grade ≥3 adverse events and immune-related events (any grade) related to a trial drug or placebo occured in 50.6% and 38.2% of patients in the dostarlimab group, respectively. More information on trial details can be found in Table 3 [Ref 15, 121, 301]

Update v1.1

Since guideline publication, pembrolizumab in combination with chemoradiotherapy was FDA-approved for patients with FIGO 2014 stage III-IVA cervical cancer [Ref 299].

This article is part of the special JITC series: Computational Immuno-Oncology

v1.1 Update

The following references have been added:

1. US Food and Drug Administration. FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel

2. Food and Drug Administration, Incyte Corp. ZYNYZ (retifanlimab) prescribing information: Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761334. Accessed 2/28/24.

3. Gross ND, Miller DM, Khushalani NI, Divi V, Ruiz ES, Lipson EJ, Meier F, Su YB, Swiecicki PL, Atlas J, Geiger JL. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. New England Journal of Medicine. 2022 Oct 27;387(17):1557-68. https://www.nejm.org/doi/10.1056/NEJMoa2209813

4. Bhatia S, Topalian SL, Sharfman WH, Meyer T, Lao CD, Fariñas-Madrid L, Devriese LA, Aljumaily R, Ferris RL, Honma Y, Khan TA. Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO)±ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC)(CheckMate 358). https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.9506

5. Kim S, Wuthrick E, Blakaj D, Eroglu Z, Verschraegen C, Thapa R, Mills M, Dibs K, Liveringhouse C, Russell J, Caudell JJ. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. The Lancet. 2022 Sep 24;400(10357):1008-19. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01659-2/abstract

v1.1 Update

Revised Panel recommendation:

• For patients with resectable CSCC at high-risk of recurrence, neoadjuvant anti-PD-1 therapy may be considered for carefully selected patients. Enrollment in clinical trials of neoadjuvant or adjuvant therapy should be offered where available.

v1.1 Update

New Panel recommendation: * Neoadjuvant anti-PD-1 therapy prior to curative-intent surgery was associated with a pCR rate of 51% and a major pathologic response rate of 13% in 70 patients with resectable stage II, III, or IV (M0) CSCC in a phase II study (LE:3). Notably, an additional 9 patients were treated but did not undergo surgery. Although not FDA-approved in this setting, neoadjuvant therapy may be considered for carefully selected patients.

v1.1 Update

Additionally, although not FDA-approved, two studies combining an anti-PD-(L)1 ICI with an anti-CTLA-4 ICI have reported efficacy in patients with recurrent/metastatic MCC. See the Recommended Immunotherapies for MCC section for more information. [Ref 180, 181].

v1.1 Update

Since guideline publication, this phase II study assessing neoadjuvant cemiplimab reported a pCR rate of 51% and a major pathologic response rate of 13% in 70 patients with resectable stage II, III, or IV (M0) CSCC. Notably, an additional 9 patients were treated but did not undergo surgery. (This regimen is not currently FDA-approved). [Ref 179]

v1.1 Update

In addition to the FDA-approved ICIs described in this section, since guideline publication, neoadjuvant anti-PD-1 therapy prior to curative-intent surgery demonstrated efficacy in a phase II study. (This regimen is not currently FDA-approved.) [Ref 179]

v1.1 Update

Since guideline publication, dual ICI therapy (anti-PD-1 + anti-CTLA-4 ICIs) has been tested in two studies of patients with recurrent/metastatic MCC. In a randomized phase II study of 50 patients, nivolumab plus ipilimumab demonstrated a 100% ORR in 24 ICI-naïve patients with unresectable, recurrent, or stage IV MCC, and an ORR of 31% in 26 patients with previous anti-PD-(L)1 therapy. In a non-randomized multicenter study of ICI-naïve patients (CheckMate 358), 68 patients received nivolumab (n = 25) or nivolumab plus ipilimumab (n = 43). The ORR was 60.0% (95% CI 38.7% to 78.9%) in the nivolumab arm and 58.1% (95% CI 42.1% to 73.0%) in the nivolumab plus ipilimumab arm. [Ref 180, 181]

v1.1 Update

Retifanlimab (an anti-PD-1 ICI) was also granted an accelerated approval by the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC [Ref 177, 178].

v1.1 Update

Retifanlimab (an anti-PD-1 ICI) was also granted an accelerated approval by the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC [Ref 177, 178].

v1.1 Update

Revised Panel recommendation: * For patients with MCC who experience disease progression while on anti-PD-(L)1 immunotherapy, therapeutic options are limited and include the addition of an anti-CTLA-4 antibody to anti-PD-(L)1 therapy, clinical trials, or chemotherapy. Switching treatments from one anti-PD-(L)1 antibody to another anti-PD-(L)1 antibody is unlikely to be beneficial.

v1.1 Update

New Panel recommendation: * Dual ICI therapy (anti-PD-1 + anti-CTLA-4 ICIs) has been tested in two studies of patients with recurrent/metastatic MCC. In a randomized phase II study of 50 patients, nivolumab plus ipilimumab demonstrated a 100% ORR in 24 ICI-naïve patients with unresectable, recurrent, or stage IV MCC, and an ORR of 31% in 26 patients with previous anti-PD-(L)1 therapy (LE:3). In a non-randomized multicenter study of ICI-naïve patients (CheckMate 358), 68 patients received nivolumab (n = 25) or nivolumab plus ipilimumab (n = 43). The ORR was 60.0% (95% CI 38.7% to 78.9%) in the nivolumab arm and 58.1% (95% CI 42.1% to 73.0%) in the nivolumab plus ipilimumab arm (LE:3). This combination is not FDA-approved for MCC, but it is reasonable to consider for select patients, especially in the PD-(L)1-refractory setting. Risk for increased toxicity with the addition of an anti-CTLA-4 agent must be carefully weighed against potential benefits in discussing dual ICI therapy with patients.

v1.1 Update

Table 2 has been updated to include the POD1UM-201 trial information and data for retifanlimab approval. See here for revised Table 2. [Ref 177, 178]

v1.1 Update

In addition to the approved ICIs for MCC described in this section, since guideline publication retifanlimab was granted accelerated approval by the FDA in March 2023 for the treatment of metastatic or recurrent locally advanced MCC. Approval was based on the POD1UM-201 trial (NCT03599713). The primary outcome measures for approval were ORR and DOR (Table 2). Safety was assessed in 105 patients with MCC, where retifanlimab was determined to be safe and well-tolerated. Serious AEs occurred in 22% of patients, and the most common serious AEs were fatigue, arrhythmia, and pneumonitis. Permanent discontinuation of therapy due to AEs occurred in 11% of patients. [Ref 177, 178]

Additionally, although not FDA-approved, two studies combining an anti-PD-(L)1 ICI with an anti-CTLA-4 ICI have reported efficacy in patients with recurrent/metastatic MCC. [Ref 180, 181]

v1.1 Update

Figure 1 has been updated to include retifanlimab as an FDA-approved ICI treatment option for patients with MCC. See updated Figure 1. [Ref 177, 178]

v1.1 Update

Retifanlimab (an anti-PD-1 ICI) was also granted an accelerated approval by the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC [Ref 177, 178].

v1.1 Update

Retifanlimab (an anti-PD-1 ICI) was also granted an accelerated approval by the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC [Ref 177, 178].

Additionally, although not FDA-approved, two studies combining an anti-PD-(L)1 ICI with an anti-CTLA-4 ICI have reported efficacy in patients with recurrent/metastatic MCC [Ref 180, 181].

v1.1 Update

Retifanlimab (an anti-PD-1 ICI) was also granted an accelerated approval by the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC [Ref 177, 178].

Last Reviewed 12/15/23 (v1.2 Update)

SITC continuously evaluates the field for practice-changing data and new FDA approvals. The information on this page provides a detailed overview of updates to the guideline content based on changes in the field. Updates to the guideline outlined below were made with the approval of SITC's Breast Cancer CPG Expert Panel. More information on SITC Guidelines can be found at sitcancer.org/guidelines.

v1.2 Update Summary

• The FDA granted accelerated approval for dostarlimab for the treatment of dMMR recurrent or advanced solid tumors (along with the VENTANA MMR RxDx Panel companion diagnostic to detect dMMR) that have progressed on or following prior treatment and who have no satisfactory alternative treatment options on August 17, 2021. Based on these approvals, the Breast Cancer CPG has been updated in the following locations: Immunotherapy with PD-(L)1 Inhibitors for the Treatment of Advanced/Metastatic Breast Cancer and Diagnostics and Biomarker Testing in Patients with Advanced/Metastatic Breast Cancer. [Ref 290]
• The FoundationOne CDx assay was approved as the companion diagnostic for identifying patients with MSI-H tumors for treatment with pembrolizumab in February 2022. Based on this approval, the Breast Cancer CPG has been updated in the following locations: Diagnostics and Biomarker Testing in Patients with Advanced/Metastatic Breast Cancer. [Ref 291]

See highlighted text for updated content and more detailed information.

v1.2 Update The following references have been added:

1. US Food and Drug Administration. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. US Food and Drug Administration. 2021. Accessed 2/29/24. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors

2. US Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Accessed 2/29/24 https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools

3. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Accessed 2/29/24: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication

4. André T, Berton D, Curigliano G, Sabatier R, Tinker AV, Oaknin A, Ellard S, de Braud F, Arkenau HT, Trigo J, Gravina A. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient solid tumors: a nonrandomized controlled trial. JAMA Network Open. 2023 Nov 1;6(11):e2341165-. https://pubmed.ncbi.nlm.nih.gov/37917058/

v1.2 Update

The FoundationOne CDx assay was approved as the companion diagnostic to identify patients with MSI-H solid tumors for pembrolizumab treatment eligibility in February 2022. [Ref 291]

v1.2 Update

Revised Panel recommendation: * Distant metastatic or recurrent tumor biopsy biomarker assessment should be considered at first relapse, including repeat receptor profiles (ER/PR/HER2), PD-L1 status, and NGS. IHC for MMR can also be considered.

v1.2 Update

Assessment of TMB, MMR, and MSI can also be considered in metastatic or recurrent lesions at first relapse to determine eligibility for the tissue-agnostic indications for pembrolizumab and dostarlimab.

v1.2 Update

Pembrolizumb and dostarlimab, were also approved in tissue-agnostic indications for the treatment of recurrent or advanced/metastatic solid tumors that are dMMR and have progressed on or following prior treatment with no satisfactory alternative treatment options in May 2017 and August 2021, respectively. [Ref 290-293]

v1.2 Update

New Panel recommendation: * For patients with recurrent or advanced dMMR breast cancer that has progressed on or following previous treatment, single agent dostarlimab or pembrolizumab may be considered (understanding that there is limited experience with breast cancer at this time).

v1.2 Update

Pembrolizumab and dostarlimab have also received FDA approvals for tissue-agnositc use for deficient mismatch repair (dMMR; as determined by an FDA-approved test) unresectable/metastatic or recurrent or advanced solid tumors, respectively, that have progressed following prior treatment and who have no satisfactory alternative treatment options. [Ref 290-292]

v1.2 Update

Table 2 has been updated to include the GARNET trial data for dostarlimab tissue agnostic approval. Updated table can be found here: [Table 2] (https://higherlogicdownload.s3.amazonaws.com/SITCANCER/2c19e5a6-3adb-4d01-b46c-c01e11745b3a/UploadedImages/CPG/SITC_Breast_CPG_v1_2_-Table_2_for_JITC_overlay__3-19-24.pdf) [Ref 290]

v1.2 Update

In addition to the approved tissue-agnostic ICI indications described in this section, since guideline publication, dostarlimab was also FDA-approved for the treatment of recurrent or advanced dMMR solid tumors that have progressed on prior therapy with no other satisfactory alternative treatment options, regardless of tissue of origin in August 2021. [Ref 290]

v1.2 Update

Dostarlimab was also granted an accelerated approval for the treatment of adult patients with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options in August 2021. Approval was based on results of the GARNET trial (NCT02715284) where 209 patients with dMMR recurrent or advanced solid tumors had an ORR of 41.6% (95% CI 34.9 to 48.6) and a median DOR of 34.7 months (range 2.6 to 35.8+). One patient with breast cancer was represented in the population assessed for approval, demonstrating a complete response. [Ref 290] Since approval of dostarlimab, an interim analysis with longer follow-up has been published. [Ref 293]

The FoundationOne CDx assay is the approved companion diagnostic for assessing MSI status for tissue-agnostic eligibility for pembrolizumab. [Ref 291]

The VENTANA MMR RxDx panel is the approved companion diagnostic for assessing MMR status for tissue-agnostic eligibility for both pembrolizumab and dostarlimab. [Ref 291]

This article is part of the special JITC series: Computational Immuno-Oncology

This article is part of the special JITC series: Computational Immuno-Oncology

This article is part of the special JITC series: Computational Immuno-Oncology

Correction underway

The dosage unit g/kg should read mg/kg for infliximab*. This unit was erroneously updated while previously correcting the dosing for IVIG and is now undergoing formal correction.

*Andruska N, Mahapatra L, Hebbard C, et al. Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep 2018;366:bcr-2018.doi:10.1136/bcr-2018-225937 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30301729

Correction underway

The dosage unit g/kg should read mg/kg for infliximab*. This unit was erroneously updated while previously correcting the dosing for IVIG and is now undergoing formal correction.

*Andruska N, Mahapatra L, Hebbard C, et al. Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep 2018;366:bcr-2018.doi:10.1136/bcr-2018-225937 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30301729

Correction underway

The dosage unit g/kg should read mg/kg for infliximab*. This unit was erroneously updated while previously correcting the dosing for IVIG and is now undergoing formal correction.

*Andruska N, Mahapatra L, Hebbard C, et al. Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep 2018;366:bcr-2018.doi:10.1136/bcr-2018-225937 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30301729

This supplement is part 1 of 2 supplements published in conjunction with the Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting. For access to the second supplement, see below.

SITC 38th Annual Meeting (SITC 2023) Abstracts Supplement 2 https://jitc.bmj.com/content/11/Suppl_2

This supplement is part 2 of 2 supplements published in conjunction with the Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting. For access to the first supplement, see below.

SITC 38th Annual Meeting (SITC 2023) Abstracts https://jitc.bmj.com/content/11/Suppl_1

Update 4-7-21

Figure 1 description has been updated, as noted below:

• Prostate carcinoma treatment algorithm: Reading from left to right, patient populations are identified. Options for treatment strategies for specific patient populations are provided in the right-most column in the corresponding row(s). All options provided are of equal preference, and selection of a treatment strategy should take into account patient- and provider-specific considerations as well as the best clinical judgement of the treating physician.

The Prostate Cancer Treatment Algorithm presented in Figure 1 has been updated in multiple areas, as noted below:

Newly Diagnosed -> Metastatic * ADT + Docetaxel * ADT + Enzalutamide * ADT + Abiraterone * ADT + Apalutamide

Recurrent ADT naïve -> Non-metastatic * ADT * Clinical trials

Recurrent ADT naïve -> Metastatic * ADT * ADT + Docetaxel * ADT + Enzalutamide * ADT + Abiraterone

CRPC -> Non-metastatic * ADT + Darolutamide * ADT + Apalutamide * ADT + Enzalutamide

mCRPC* > Minimal/no symptoms * Sipuleucel-T

mCRPC* -> Symptomatic bone-metastases * Radium-23

mCRPC* -> Symptomatic or asymptomatic * Enzalutamide * Abiraterone * Docetaxel * Clinical trial

mCRPC* -> Post-abiraterone or post-enzalutamide * Olaparib(%)

mCRPC* -> Post-docetaxel * Cabazitaxel * Rucaparib(#)

Updated treatment table

Figure 1 footnotes have been updated, as noted below:

• Although not available at the time of publication, for patients with TMB-H or MSI-H/dMMR tumors, pembrolizumab or dostarlimab may be considered, based on FDA-approved indications. (1) Metastasis defined by positive technetium bone scan or CT scan

(*) Treatment with continuous testosterone suppression, and with or without denosumab or zoledronic acid

(#) Patients with deleterious germline or somatic BRCA mutation who have been treated with taxane-based chemotherapy

(%) Patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutation who have progressed after treatment with enzalutamide or abiraterone

This article is part of the special JITC series: Microbial-Based Cancer Immunotherapy

This article is part of the special JITC series: Microbial-Based Cancer Immunotherapy

This article is part of the special JITC series: Microbial-Based Cancer Immunotherapy

This article is part of the special JITC series: Microbial-Based Cancer Immunotherapy

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Immune Monitoring Technology Primers

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Emerging Immunotherapeutic Agents

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: Immune Checkpoints Beyond PD-1

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: COVID-19 and Cancer Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

This article is part of the special JITC series: Imaging and Immunotherapy

test

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This review has a companion letter: Brave new world of cfDNA-omics for early cancer detection

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This viewpoint letter refers to a companion review: [Cell-free DNA approaches for cancer early detection and interception] (https://jitc.bmj.com/content/11/9/e006013)

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

Update 8-1-2023

The mUC treatment algorithm has been updated based on the label change for pembrolizumab, the voluntary withdrawal of the atezolizumab indication, and the approval of pembrolizumab plus enfortumab vedotin for the treatment of patients with advanced mUC.

Updated mUC treatment algorithm

This is a companion letter corresponding with the review: Genomic approaches to cancer and minimal residual disease detection using circulating tumor DNA

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This review has a companion letter: Challenges in the implementation of ultrasensitive liquid biopsy approaches in precision oncology

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This is a companion letter corresponding with the review: Regulatory implications of ctDNA in immuno-oncology for solid tumors

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This review has a companion letter: Liquid biopsies, are we ready for prime time?

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This review has a companion letter: Next-generation ctDNA-driven clinical trials in precision immuno-oncology

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This is a companion letter corresponding with the review: Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This is a companion letter corresponding with the review: Crucial roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

This review has a companion letter: Comments on roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation

This article is part of the special JITC series: Liquid Biopsies Coming of Age: Biology, Emerging Technologies, and Clinical Translation

SITC continuously evaluates the field for emerging data and new FDA approvals. Updates to the recommendations, tables, treatment algorithms, and/or guideline text in this publication are made with the approval of the SITC Urothelial Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

Update 8-17-22

Based on advances in the field, including the following three FDA approvals and ongoing trials, the RCC CPG has been updated throughout the entire manuscript:

(1) Pembrolizumab for the adjuvant treatment of RCC: In November of 2021, the FDA approved pembrolizumab (anti-PD-1) for the adjuvant treatment of resected RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Reference: FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma FDA press release

(2) Pembrolizumab plus lenvatinib for the treatment of advanced RCC: In August of 2021, the FDA approved pembrolizumab in combination with lenvatinib (a VEGF receptor tyrosine kinase inhibitor; TKI) for the first-line treatment of patients with advanced RCC (aRCC).

Reference: FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma FDA press release

(3) Nivolumab plus cabozantinib for the treatment of advanced RCC: In January of 2021, the FDA approved nivolumab (anti-PD-1) in combination with cabozantinib (a VEGF receptor TKI) for the first-line treatment of patients with aRCC.

Reference: FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma FDA press release

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For first-line treatment of patients with unresectable, metastatic clear cell RCC and a remote history of a non-life threatening autoimmune condition, irrespective of IMDC risk status, the Expert Panel recommends the following: pembrolizumab plus lenvatinib (23%), nivolumab plus ipilimumuab (23%), nivolumab plus cabozantinib (15%), appropriate anti-VEGF TKI monotherapy (15%), pembrolizumab plus axitinib (15%), or anti-PD-1 monotherapy (8%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for the use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For first-line treatment for patients with chromophobe RCC, the Expert Panel recommends the following: VEGF TKI plus ICI (40%: lenvatinib plus pembrolizumab [3 Expert Panel members], cabozantinib plus nivolumab [2 Expert Panel members], axitinib plus pembrolizumab [1 Expert Panel member]), lenvatinib plus everoliums (40%), everolimus (7%), or everolimus plus bevacizumab (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For first-line treatment for patients with papillary RCC, the Expert Panel recommends the following: nivolumab plus cabozantinib (87%), mivolumab plus ipilimumab (7%), or anti-PD1 monotherapy (7%).

For first-line treatment for patients with undifferentiated RCC, the Expert Panel recommends the following: VEGF TKI plus ICI (53%: nivolumab plus cabozantinib [4 Expert Panel members], pembrolizumab plus lenvatinib [4 Expert Panel members]), or nivolumab plus ipilimumab (47%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approval for use of adjuvant pembrolizumab for RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, the following text was added:

For patients with nccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of isolated soft tissue metastases, 80% of the Expert Panel disagreed that adjuvant pembrolizumab is recommended (presuming that the patient has an acceptable performance status and no contraindications to checkpoint inhibitor therapy).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was modified as follows:

For first-line treatment for patients with sarcomatoid RCC irrespective of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors, the Expert Panel recommends: nivolumab plus ipilimumab (80%), pembrolizumab plus axitinib (13%), or nivolumab plus cabozantinib (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approval for use of adjuvant pembrolizumab for RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, this text was modified as follows:

For patients who develop unresectable metastatic RCC at or beyond 6 months following adjuvant pembrolizumab (presuming that the patient has an acceptable performance status and no contraindications to checkpoint inhibitor therapy or any TKI), the Expert panel recommends the following: ICI plus TKI (47%), cabozantinib plus nivolumab (2 Expert Panel members), lenvatinib plus pembrolizumab (3 Expert Panel members), nivolumab plus ipilimumab (53%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approval for use of adjuvant pembrolizumab for RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, this text was modified as follows:

For patients who develop unresectable metastatic RCC during or within 6 months of receiving adjuvant pembrolizumab (presuming that the patient has an acceptable performance status and no contraindications to checkpoint inhibitor therapy or any TKI), the Expert panel recommends the following: nivolumab plus ipilimumab (33%), single agent TKI (27%), ICI plus TKI (20%), pembrolizumab plus lenvatinib (2 Expert Panel members), nivolumab plus cabozantinib (1 Expert Panel member), lenvatinib plus everolimus (7%), or other/ unsure of what would be best in this setting (7%).

Update 8-17-22

Subheader changed to the following: SOC in adjuvant setting (including ongoing trials)

Update 8-17-22

Upon survey of the Expert Panel following the FDA approval for use of adjuvant pembrolizumab for RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, the following text was added:

For patients with resected ccRCC and no contraindications to immunotherapy, this expert panel recommends adjuvant pembrolizumab for: all patients meeting inclusion criteria for KEYNOTE-564 (60%), only higher risk patients eg, T4 or N+ (27%), or no patients until there is a statistically significant OS advantage (13%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For a patient who has progressed after lenvatinib plus pembrolizumab combination therapy, the Expert Panel recommends the following: <br /> cabozantinib (73%), ipilimumab plus nivolumab (13%), lenvatinib plus everolimus (7%), cabozantinib plus nivolumab (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For a patient who has progressed after cabozantinib plus nivolumab combination therapy, the Expert Panel recommends the following: lenvatinib plus everolimus (67%), nivolumab plus ipilimumab (13%), tivozanib (7%), everolimus (7%), or lenvatinib + pembrolizumab (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For a patient who has progressed after axitinib plus pembrolizumab combination therapy, the Expert Panel recommends the following: cabozantinib (67%), ipilimumab plus nivolumab (13%), lenvatinib plus everolimus (7%), cabozantinib plus nivolumab (7%), or lenvatinib plus pembrolizumab (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For first-line treatment of patients with unresectable, metastatic VHL-associated ccRCC, the Expert Panel recommends the following: belzutifan (53%), nivolumab plus ipilimumab (27%), or cabozantinib plus nivolumab (20%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For first-line treatment of patients with unresectable, metastatic clear cell RCC and a remote history of a non-life threatening autoimmune condition, irrespective of IMDC risk status, the Expert Panel recommends the following: pembrolizumab plus lenvatinib (23%), nivolumab plus ipilimumuab (23%), nivolumab plus cabozantinib (15%), appropriate anti-VEGF TKI monotherapy (15%), pembrolizumab plus axitinib (15%), or anti-PD-1 monotherapy (8%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, the following text was added:

For a treatment naïve, ECOG ≥ 1 ccRCC patient with “poor” risk per IMDC, who is determined to need systemic therapy and has no contraindication to receiving either an IO or an anti-VEGF therapy, the Expert Panel recommends the following: nivolumab plus ipilimumab (47%), VEGF TKI plus checkpoint inhibitor combination (23%: pembrolizumab plus lenvatinib [17%], pembrolizumab plus axitinib [11%], nivolumab plus cabozantinib [11%], pembrolizumab or nivolumab monotherapy [6%]).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For a treatment naïve, ECOG 0 ccRCC patient with “favorable” risk per IMDC, who is determined to need systemic therapy and has no contraindication to receiving either an IO or anti-VEGF therapy, the Expert Panel recommends the following: TKI plus anti-PD1 (60%), nivolumab plus ipilimumab (33%), or anti-PD1 monotherapy (7%).

Update 8-17-22

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For first-line VEGF TKI + checkpoint inhibitor combination therapy for RCC, the Expert Panel recommends the following: cabozantinib plus nivolumab (40%), lenvatinib plus pembrolizumab (33%), axitinib plus pembrolizumab (20%), and not applicable ("I would never choose a VEGF TKI plus checkpoint inhibitor combination for this population").

Algorithm updated 8-17-22

(1) Pembrolizumab for the adjuvant treatment of RCC: In November of 2021, the FDA approved pembrolizumab (anti-PD-1) for the adjuvant treatment of resected RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. - This approval was based on a statistically significant improvement in DFS demonstrated at a prespecified interim analysis of the KEYNOTE-564 study, with 109 (22%) events in the pembrolizumab arm and 151 (30%) events in the placebo (HR 0.68; 95% CI: 0.53, 0.87; p=0.0010). The November of 2021 FDA approval of pembrolizumab for the adjuvant treatment of resected RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, was based on data from the KEYNOTE-564 study. This study demonstrated a statistically significant improvement in DFS at a pre-specified interim analysis, with 109 (22%) events in the pembrolizumab arm and 151 (30%) events in the placebo (HR 0.68; 95% CI: 0.53, 0.87; p=0.0010).

Upon survey of the Expert Panel following the FDA approvals for use of first-line pembrolizumab plus lenvatinib or nivolumab plus cabozantinib for aRCC, this text was modified as follows:

For a treatment naïve, ECOG 0 ccRCC patient with “intermediate/poor” risk per IMDC, who is determined to need systemic therapy and has no contraindication to receiving either an IO or an anti-VEGF therapy, the Expert Panel recommends the following: nivolumab plus ipilimumab (80%), anti-PD1 plus TKI (20%, with 53% preferring nivolumab plus cabozantinib and 40% preferring pembrolizumab plus lenvatinib), or other (7% preferring lenvatinib + everolimus).

The August 2021 FDA approval of pembrolizumab in combination with lenvatinib for the first-line treatment of patients with aRCC was based on a statistically significant improvement in PFS and OS in CLEAR (Study 307/ KEYNOTE-581). Patients receiving pembrolizumab plus lenvatinib had a median PFS of 23.9 months versus 9.2 months for those receiving sunitinib (HR 0.39; 95% CI: 0.32 to 0.49; p<0.0001). Median OS was not reached in either arm (HR 0.66; 95% CI: 0.49 to 0.88; p=0.0049).

The January 2021 FDA approval of nivolumab in combination with cabozantinib for the first-line treatment of patients with aRCC was based on a statistically significant improvement in PFS, OS, and ORR in the CHECKMATE-9ER study. Patients receiving nivolumab plus cabozantinib had a median PFS of 16.6 months versus 8.3 months for those receiving sunitinib (HR 0.51; 95% CI: 0.41, 0.64). Median OS was not reached in either arm (HR 0.60; 95% CI: 0.40 to 0.89). ORR was 55.7% versus 27.1% in the nivolumab plus cabozantinib and sunitinib arms, respectively.