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.

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, FDA-Approved ICI agents for NMSC, NMSC Landmark Clinical Trial Data Leading to FDA Approvals for ICIs for MCC, and Novel Stretegies 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: Recommanded 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.

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

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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

Update 8-1-2023

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.

Update 8-1-2023

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.

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.

Reference: Adstiladrin (Nadofaragene firadenovec, Ferring Pharmaceuticals) package insert

https://www.fda.gov/media/164029/download

Update 8-1-2023

Revised recommendation: Pembrolizumab is approved for the treatment of high-risk BCG-unresponsive CIS with or without papillary tumors (LE:2). Nadofaragene firadenovec-vncg is also approved for the treatment of high-risk BCG-unresponsive CIS with or without papillary tumors (LE:2).

Update 8-1-2023

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.

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.

Reference: Adstiladrin (Nadofaragene firadenovec, Ferring Pharmaceuticals) package insert https://www.fda.gov/media/164029/download

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 8-1-2023

Based on the voluntary withdrawal by the manufacturer of the atezolizumab indication for the treatment of cisplatin- and platinum-ineligible patients with mUC, the Urothelial Cancer CPG has been updated in the Diagnostic tests and biomarkers for urothelial cancer immunotherapy, Advanced/metastatic urothelial carcinoma, and the mUC treatment algorithm sections.

Based on the approval of nadofaragene firadenovec for the treatment of BCG-unresponsive NMIBC with CIS with or without papillary tumors, the Urothelial Cancer CPG has been updated in the Non-muscle invasive bladder cancer section.

Reference: [Nadofaragene firadenovec (Adstiladrin, Ferring Pharmaceuticals) FDA press release] (https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-high-risk-non-muscle-invasive-bladder-cancer)

Based on the 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, the Urothelial Cancer CPG has been updated in the Advanced/metastatic urothelial carcinoma and mUC treatment algorithm sections.

Reference: Pembrolizumab (Keytruda, Merck & Co, Inc) plus enfortumab vedotin (Padcev, Astellas Pharma) FDA press release

Update 8-24-2022

Based on the indication change for pembrolizumab for the treatment of patients with mUC, the Urothelial Cancer CPG has been updated in the following locations: - Immunotherapies for First-line Treatment of mUC - mUC Treatment Algorithm

Update 9-21-2021

Based on the approval of nivolumab for the treatment of patients with urothelial cancer who are at high risk of recurrence after undergoing radical resection, the Urothelial Cancer CPG has been updated in the following locations: - Phase III trials of adjuvant therapy for MIBC - Immunotherapy with chemoradiation as bladder-sparing therapy - Table 5 - mUC treatment algorithm - Immunotherapies for first-line treatment of mUC - Immunotherapies for R/R mUC

Reference: Nivolumab (Opdivo) FDA press release

Update 9-21-2021

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

• The FDA granted priority review status to the Biologics License Application for nivolumab for adjuvant treatment of patients with surgically resected, high-risk MIBC in April 2021, and subsequently approved nivolumab for the treatment of patients with urothelial cancer (UC) who are at high risk of recurrence after undergoing radical resection in August 2021.

Update 9-21-2021

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.

Update 8-24-2022

Modification below reflects the indication change for pembrolizumab for the first-line treatment of patients with mUC:

• …in May 2017, the FDA approved pembrolizumab for use as a first-line treatment of mUC in any patient ineligible for platinum-based chemotherapy regardless of PD-L1 status.

Update 9-21-2021

At the conclusion of this sentence, the modification below is added to include information on the approval of nivolumab as adjuvant treatment for patients with surgically resected, high-risk MIBC.

• Full approval of nivolumab in this setting was granted in August, 2021.

Update 8-1-2023

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

Update 8-1-2023

Since the original publication of this guideline, the indication for pembrolizumab for the treatment of patients with locally advanced or metastatic UC ineligible for platinum-containing chemotherapy or with disease progression on or after platinum-containing chemotherapy no longer specifies PD-L1 expression for treatment eligibility. Additionally, the indication for atezolizumab for the treatment of metastatic or locally advanced UC was voluntarily withdrawn by the manufacturer.

Update 8-1-2023

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.

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.

Update 8-1-2023

Since the original guideline publication, the 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.

Updated NMIBC immunotherapy treatment algorithm

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

Update 8-1-2023

Revised recommendation: The first-line SOC for cisplatin-eligible patients with mUC is cisplatin-based chemotherapy. For patients who are cisplatin-ineligible, carboplatin-based chemotherapy or enfortumab vedotin plus pembrolizumab (LE: 2) are standard options. For patients who are chemotherapy-ineligible, pembrolizumab can be considered.

Update 8-1-2023

Footnote added to the Large phase II and III clinical trials investigating ICIs for mUC, as noted below:

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

Update 8-1-2023

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.

Update 8-1-2023

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.

Update 8-1-2023

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.

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.

Reference: Pembrolizumab (Keytruda, Merck & Co, Inc.) package insert https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136.pdf

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.

Update 8-27-2021

To add additional guidance on the management of patients with ICI-related hypophysitis and severe compressive symptoms, this recommendation was updated, as noted below:

• Patients with hypophysitis should receive replacement hydrocortisone at 10–12 mg/m2/day; a short-course of prednisone 1mg/kg (or equivalent) may be given for patients with severe compressive symptoms (e.g. headache, double vision).

Update October 2022

The recommendation on baseline troponin testing has been updated, as noted below:

• Consider performing a baseline electrocardiogram (EKG) and baseline troponin testing on patients deemed at a higher risk for myocarditis (eg, cardiac comorbidities, diabetes mellitus, ICI combination regimens including dual ICIs or VEGF TKIs, etc). Patients receiving ICI plus VEGF TKIs who have elevated baseline troponin T should be closely monitored for major cardiac adverse events.

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 Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines

Update October 2022

In response to recent data regarding increased risk for MACE in patients with RCC receiving ICI + VEGF TKI therapy, the ICI-related Adverse Events Guideline was updated in the following location: * General Expert Panel Recommendations

Reference: Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Cancer: Data From the Phase III JAVELIN Renal 101 Trial

Update 8-7-2021

To add additional guidance on the management of patients with ICI-related hypophysitis and severe compressive symptoms, the ICI-related Adverse Events CPG was updated in the following location: * Endocrine Toxicity Expert Panel Recommendations

Update 2-9-2021

Immunotherapies in Development for NHL table updated to remove lisocabtagene maraleucel from list of agents in development.

The following row describing TRANSCEND-NHL-001 has been removed from the table "Immunotherapies in development for the treatment of non-Hodgkin lymphoma":

• TRANSCEND-NHL-001 (NCT02631044)
• Agents Investigated: Lisocabtagene maraleucel
• Agent Description: CAR T cell
• Primary Outcome for Assessment: Treatment-related AEs, dose-limiting toxicities, ORR

Update 2-9-2021

Recommendation updated to include lisocabtagene maraleucel as a third-line treatment option for PMBCL, as noted below:

• The panel did not reach consensus on a specific treatment regimen for the third-line treatment of PMBCL. Treatment options include axicabtagene ciloleucel, lisocabtagene maraleucel, BV+pembrolizumab, or appropriate salvage chemotherapy regimens.

Update 10-22-2022

Recommendation updated to reflect the approval of lisocabtagene maraleucel and tisagenlecleucel as a third-line treatments for follicular lymphoma, as noted below:

• There was consensus that second-line (or later) treatment regimens for patients with FL will vary, and should be decided on a case-by-case basis using factors that include prior therapies, time of relapse, tumor bulk, age, and comorbidity status. Ibritumomab tiuxetan may be used in this context, if deemed appropriate. Lisocabtagene maraleucel is approved for FL grade 3B after two or more lines of systemic therapy. Axicabtagene ciloleucel and tisagenlecleucel are approved for adult patients with FL after two or more lines of therapy.

Update 2-9-2021

Recommendation updated to include lisocabtagene maraleucel as third-line treatment option for DLBCL, as noted below:

• There was consensus that the third-line treatment for DLBCL in fit patients should be anti-CD19 CAR T cell therapy (axicabtagene ciloleucel, lisocabtagene maraleucel, or tisagenlecleucel).

Update 10-22-2022

Recommendation updated to reflect the approval of lisocabtagene maraleucel as a second-line treatment for transplant-ineligible patients with DLBCL, as noted below:

• For second-line therapy of DLBCL in patients who are transplant-ineligible, options include lisocabtagene maraleucel, lenalidomide, lenalidomide+tafasitamab-cxix, polatuzumab vedotin-piiq+BR or an appropriate salvage chemoimmunotherapy regimen (including R-GemOx or R-GDP).

Update 10-22-2022

Recommendation updated to reflect the appropriate setting for non-CAR T cell options as second-line treatments for refractory DLBCL, as noted below:

• For the second-line therapy of DLBCL that has relapsed > 12 months after receiving first-line chemoimmunotherapy, transplant-eligible patients should receive a chemoimmunotherapy regimen that includes rituximab (such as rituximab+ICE (R-ICE) or rituximab+dexamethsone+cytarabine+cisplatin (R-DHAP)), followed by autoSCT consolidation if CR is achieved.

Update 10-22-2022

Recommendation added for second-line use of axicabtagene ciloleucel and lisocabtagene maraleucel, as noted below:

• For the second-line therapy of DLBCL that is refractory to first-line chemoimmunotherapy or relapses within 12 months of chemoimmunotherapy, patients should receive axicabtagene ciloleucel or lisocabtagene maraleucel.

Update 10-22-2022

Description of tisagenlecleucel updated to include disease states specified in FDA approval, including the addition of follicular lymphoma, as noted below:

• Tisagenlecleucel is FDA-approved for the treatment of R/R large B cell lymphomas (including DLBCL not otherwise specified, high grade B cell lymphoma, and DLBCL arising from FL) and FL after two or more prior lines of systemic therapy.

Update 10-22-2022

Description of axicabtagene ciloleucel approved indications updated to include second-line treatment of large B-cell lymphoma, as noted below:

• Axicabtagene ciloleucel is FDA-approved for second-line treatment of large B-cell lymphoma and the treatment of R/R large B cell lymphomas (including DLBCL, PMBCL, high-grade B cell lymphoma, and transformed FL) after two or more prior lines of systemic therapy.

Update 10-22-2022

Description of lisocabtagene maraleucel approvals and indications added, as noted below:

• Lisocabtagene maraleucel is approved for the treatment of R/R large B cell lymphomas – including DLBCL not otherwise specified, DLBCL arising from indolent lymphoma, high-grade B cell lymphoma, primary mediastinal large B cell lymphoma, and FL grade 3B – who have refractory disease to first-line chemoimmunotherapy, or relapse within 12 months of first-line chemoimmunotherapy as well as later relapse in transplant-ineligible patients. Lisocabtagene maraleucel is also approved as third-line or later treatment.

Update 6-3-2021

Description of loncastuximab tesirine-lpyl approval and indication added, as noted below:

• On April 23, 2021, the a CD19-directed antibody and alkylating agent conjugate loncastuximab tesirine-lpyl received accelerated approval for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLCBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

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

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

Update 4-9-2021

Information on idecabtagene vicleucel approval data and indication has been added, as noted below:

• Idecabtagene vicleucel is a BCMA-directed CAR T cell therapy, indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Approval was based on safety and efficacy in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who had received at least three prior lines of antimyeloma therapies with 88% having received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel at a dose range of 300 to 460 x 106 CAR-positive T cells. The ORR (by IMWG criteria) was 72% (95% CI, 62% to 81%) and CR rate was 28% (95% CI, 19% to 38%). An estimated 65% of patients who achieved CR remained in CR for at least 12 months. The expert panel recommendations on CAR T cell therapy for multiple myeloma were developed, in part, based on experience from trials of idecabtagene vicleucel.

Update 8-5-2020

A recommendation has been added, as noted below:

• Avoid use of contact lenses unless directed by an opthamologist during treatment with belantamab mafadotin.

Update 8-5-2020

The following recommendation has been removed:

• During belantamab mafodotin treatment specifically, therapy can be restarted once keratopathy or other AEs (such as cytopenias) have resolved to grade 1 or less. Dose reduction from 3.4 to 2.5 mg/kg may be considered. Further dose reductions to 1.9 mg/kg may be done if significant toxicity recurs.

Update - 8-5-2020

A recommendation was updated, as noted below:

• Belantamab mafadotin should be withheld in the event of moderate to severe corneal toxicity, then restarted with a reduced dose once symptoms resolve

Update 8-5-2020

A recommendation was updated, as noted below:

• Patients being treated with belentamab mafadotin should be advised to use preservative-free eye drops at least 4 times per day starting with the first infusion and continuing until end of treatment.

Update 8-5-2020

A recommendation was updated, as noted below:

• Patients should be routinely monitored with complete blood counts and complete metabolic panels.

Update 8-5-2020

An additional recommendation was added, as noted below:

• Belantamab mafadotin is approved for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 mAb, a proteasome inhibitor and an immunomodulatory agent

Update 8-5-2020

The approval status and information regarding Belantamab mafadotin has been updated, as noted below:

• Belantamab mafadotin, an anti-BCMA antibody conjugated to the cytotoxic monomethyl auristatin F via a non-cleavable linker, received accelerated approval for relapsed or refractory multiple myeloma in August, 2020. Approval was based on the open-label, multicenter trial DREAMM-2 (NCT 03525678). Because of the risks of ocular toxicity, belantamab mafodotin is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the BLENREP REMS.

Update August 2022

Text has been added to the introduction to include updated information on pembrolizumab and dostarlimab tissue-agnostic approvals, as noted below:

• Since the guideline’s original publication, pembrolizumab was subsequently approved by FDA for the treatment of tumors with high tumor mutation burden (TMB-H) as well as mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) cancers, which includes a small number of advanced prostate tumors. Dostarlimab (anti-PD-1) has also been approved by the FDA for the treatment of dMMR tumors.

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 Prostate Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

Update August 2022

Based on the tissue agnostic approvals for pembrolizumab for the treatment of TMB-H and MSI-H/dMMR solid tumors and dostarlimab for the treatment of dMMR solid tumors, and their approved companion diagnostics, the Prostate Cancer CPG has been updated in the following location: - Introduction

References: Pembrolizumab (KEYTRUDA) TMB-H tissue-agnostic approval

Pembrolizumab (KEYTRUDA) MSI-H/dMMR tissue-agnostic approval

Dostarlimab (JEMPERLI) dMMR tissue-agnostic approval

Update 8-24-22

Based on new approvals of immunotherapy agents for the treatment of prostate cancer and new data that has been published since its original publication, the Prostate CPG was updated in the following locations: - Figure 1 - Prostate Cancer Treatment Algorithm

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 Multiple Myeloma Cancer Immunotherapy Guideline Expert Panel. More information on the SITC Guidelines can be found at sitcancer.org/guidelines.

Update 2-1-2022

Based on the FDA approval of daratumumab in combination with carfilzomib and dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy on November 30, 2021, the Multiple Myeloma CPG has been updated in the following locations: * Monoclonal Antibodies Expert Panel Recommendations * Multiple Myeloma Key Monoclonal Antibody Therapies Trials

Reference: Daratumumab + hyaluronidase-fihj (Darzalex Faspro, Janssen Biotech, Inc.) and carfilzomib (Kyprolis, Amgen, Inc.) plus dexamethasone press release

Update 4-9-2021

Based on the approval of idecabtagene vicleucel for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, the Multiple Myeloma CPG has been updated in the following locations: * Background * CAR T cell Therapies

Reference: Idecabtagene vicleucel (ABECMA) FDA press release

Based on the approval of isatuximab-irfc in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy, the Multiple Myeloma CPG has been updated in the following locations: * Monoclonal Antibody Therapies * Multiple Myeloma Key Monoclonal Antibody Therapies Trials

Reference: Isatuximab-irfc (SARCLISA) FDA press release

Update 8-5-2020

Based on the accelerated approval of belantamab mafodotin-blmf for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent, the Multiple Myeloma CPG was updated in the following locations: * Antibody-Drug Conjugates * Background

Reference: Belantamab mafodotin-blmf (BLENREP) FDA press release