Malignant solid neoplasm, MSI-H or dMMR

4 regimens on this page 6 variants on this page

Guidelines

JSCO/ESMO/ASCO/JSMO/TOS

• 2020: Yoshino et al. JSCO—ESMO—ASCO—JSMO—TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions

All lines of therapy

Dostarlimab monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Patnaik et al. 2021 (GARNET)	2017-2019	Phase 1 (RT)

Note: dosing is as provided in the FDA release.

Immunotherapy

• Dostarlimab (Jemperli) as follows:
  • Cycles 1 to 4: 500 mg IV over 30 minutes once on day 1
  • Cycle 5 onwards: 1000 mg IV over 30 minutes once on day 1

21-day cycle for 4 cycles, then 42-day cycles

References

1. GARNET: Patnaik A, Weiss GJ, Rasco DW, Blaydorn L, Mirabella A, Beeram M, Guo W, Lu S, Danaee H, McEachern K, Im E, Sachdev JC. Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose-escalation phase 1 trial. Cancer Chemother Pharmacol. 2022 Jan;89(1):93-103. Epub 2021 Nov 8. link to original article link to PMC article PubMed Clinical Trial Registry

Envafolimab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Li et al. 2021 (KN035-CN-006)	2018-2019	Phase 2

Immunotherapy

• Envafolimab (KN 035) 150 mg SC once per day on days 1, 8, 15, 22

28-day cycles

References

1. Li J, Deng Y, Zhang W, Zhou AP, Guo W, Yang J, Yuan Y, Zhu L, Qin S, Xiang S, Lu H, Gong J, Xu T, Liu D, Shen L. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol. 2021 Jun 21;14(1):95. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry

Pembrolizumab monotherapy

Regimen variant #1, q2wk dosing

Study	Dates of enrollment	Evidence
Le et al. 2015 (KEYNOTE-016)	2013-2015	Phase 2 (RT)

Note: this was an expansion to a CRC-specific trial.

Biomarker eligibility criteria

• Protein: MMR
• Alteration: dMMR

Immunotherapy

• Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

14-day cycles

Regimen variant #2, q3wk, adult dosing

FDA-recommended dose

Study	Dates of enrollment	Evidence
Le et al. 2019 (KEYNOTE-164)	2015-2017	Phase 2 (RT)
Marabelle et al. 2019 (KEYNOTE-158) ESMO-MCBS (3)	2016-2018	Phase 2 (RT)

Note: this is the FDA-approved adult pembrolizumab dose and schedule based on a pooled analysis of 5 non-randomized trials, of which two were prospective: KEYNOTE-158 and KEYNOTE-164.

Biomarker eligibility criteria

• KEYNOTE-164
  • Protein: MMR
  • Alteration: dMMR
  • Acceptable methods of measurement: IHC
• KEYNOTE-158
  • Protein: PD-L1
  • Alteration: expression
  • Acceptable methods of measurement: IHC

Prior treatment criteria

• KEYNOTE-164: prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and, if KRAS and NRAS wild type, cetuximab or panitumumab; no prior anti-cancer therapy within last 2 weeks

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1

21-day cycle for up to 35 cycles (2 years)

Regimen variant #3, q3wk, pediatric dosing

FDA-recommended dose

Study	Dates of enrollment	Evidence
Le et al. 2019 (KEYNOTE-164)	2015-2017	Phase 2 (RT)
Marabelle et al. 2019 (KEYNOTE-158) ESMO-MCBS (3)	2016-2018	Phase 2 (RT)

Note: this is the FDA-approved pediatric pembrolizumab dose and schedule based on a pooled analysis of 5 non-randomized trials, of which two were prospective: KEYNOTE-158 and KEYNOTE-164.

Biomarker eligibility criteria

• KEYNOTE-164
  • Protein: MMR
  • Alteration: dMMR
  • Acceptable methods of measurement: IHC
• KEYNOTE-158
  • Protein: PD-L1
  • Alteration: expression
  • Acceptable methods of measurement: IHC

Prior treatment criteria

• KEYNOTE-164: prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and, if KRAS and NRAS wild type, cetuximab or panitumumab; no prior anti-cancer therapy within last 2 weeks

Immunotherapy

• Pembrolizumab (Keytruda) 2 mg/kg (maximum dose of 200 mg) IV over 30 minutes once on day 1

21-day cycle for up to 35 cycles (2 years)

References

1. KEYNOTE-016: Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
   1. Update: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. link to original article link to PMC article contains dosing details in supplement PubMed
2. KEYNOTE-164: Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, Burge M, O'Neil B, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Crocenzi T, Atreya CE, Cui Y, Dai T, Marinello P, Diaz LA Jr, André T. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020 Jan 1;38(1):11-19. Epub 2019 Nov 14. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
3. KEYNOTE-158: Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020 Jan 1;38(1):1-10. Epub 2019 Nov 4. link to original article link to PMC article PubMed Clinical Trial Registry
   1. Update: Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH, Oh DY, Gottfried M, Xu L, Jin F, Norwood K, Marabelle A. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022 Sep;33(9):929-938. Epub 2022 Jun 6. link to original article PubMed