KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:…for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Acceptable Recurrence Therapies for…Peritoneal Cancer: Useful in certain circumstances…Immunotherapy...Pembrolizumab (for microsatellite instability-high [MSI-H] or mismatch repair-deficient [dMMR] dolid tumors)

...Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors and Other Lymphoma Version 1.1 (RECIST 1.1) per Site Assessment (Each Disease Indication Evaluated Separately)`ORR by RECIST 1.1 per Site Assessment for MSI-H or TMBH Solid Tumors (Each Cohort Evaluated Separately)`ORR by International Working Group (IWG) Response Criteria (Cheson, 2007) per BICR Assessment for rrcHL Cohort`Number of Participants with Dose-Limiting Toxicities (DLTs)`Number of Participants Experiencing Adverse Events (AEs)`Number of Participants Discontinuing Study Drug Due to AEs...

...- Patients must have deficient mismatch repair as demonstrated by lack of expression of at least one mismatch repair protein by immunohistochemistry (IHC) and/or evidence of microsatellite instability (MSI) high....

...- Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed primary diagnosis of dMMR/POLE-EDM uterine cancer who are intended to be treated with hysterectomy will be enrolled in this study....

...- Locally confirmed dMMR or MSI-H stage IV colorectal carcinoma...

...1.Adult male or female patients aged 18 years or older.2.Be willing and able to provide written informed consent for the study.3.Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable:• A: Non-squamous NSCLC.• B: Cervical cancer.• C: MSS-CRC.• D: Cutaneous melanoma.• E: Squamous NSCLC.• F: Small cell lung cancer.• G: HNSCC.• H: MSI-H/dMMR CRC.Note: For further details, please refer to protocol.4.Have at least 1 radiologically measurable lesion based on RECIST, Version 1.1. ...

...MSKCC confirmation of MSI-H/MRD status is...

...and Deficient MMR status (IHC) or MSI-High status (PCR) (cohort D only)....

...- Locally confirmed MMR deficient or MSI-H status...

...Histologically confirmed localized dMMR stage cT1N0M0 to cT4N2M0 (stage I to III) colon carcinoma....

...Histologically proven adenocarcinoma of the colon or rectum which is MMR-d by IHC or MSI-H by PCR (or microsatellite testing if routine practice)....

...(Only Cohort B) confirmed as MSI-H via the PCR or IHC staining by institutional standard....

...- Subjects with histologically confirmed melanoma, NSCLC, transitional cell carcinoma of the GU tract, TNBC, SCCHN, ovarian cancer, MSI high colorectal cancer (CRC), RCC, gastric cancer, HCC and DLBCL (Phase 2)....

...Colorectal cancer liver metastases (CRC-LM) gene test was MSI-H/dMMR. ...

...• Signed written informed consent; • Patients at least 18 years of age; • Locally advanced, irresectable adenocarcinoma of the colon or rectum, not amenable to surgery, or for which induction therapy is required to reconsider surgery, or where free margins can only be obtained by major extension of the surgical procedure, as defined by one of the following: o Invasion of the duodenum, stomach, spleen or pancreatic head, for which major extension of the surgical procedure would be required to obtain free margins, and/or for which the chances of positive resection margins are high o Invasion or encasement of major blood vessels (superior mesenteric vessels, iliac vessels, portal vein) o Invasion or encasement of the ureter • Histologically or cytologically confirmed microsatellite instability-high (MSI-H) or MMR-deficient (dMMR) status• No signs of distant metastases on CT-scan and physical examination; patients may not be eligible for first-line treatment with pembrolizumab according to SoC • Patients may not be eligible for standard of care first-line pembrolizumab for metastatic disease • Patients may not be potentially eligible for the NICHE study: patients with primarily resectable disease, for which relatively minor extension of the procedure is required to acieve free margins, such as but not limited to a small bowel segment, abdominal wall• ECOG performance status of 0 or 1. ...

...Microsatellite Instability-High Cancer 9....

...One year PSA (Prostate Specific Antigen) failure rate`Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v4.0`Number of participants with decrease in SUV uptake after 3 cycles of pembrolizumab`Assess a possible correlation between deficient mismatched repair (dMMR) and microsatellite instability-high (MSI-H) and response to pembrolizumab.`...

...Previously treated participants with solid tumors (NSCLC, melanoma, HNSCC, RCC, HCC, gastroesophageal carcinomas, UC, or CRC [MSI-H]) for whom, in the opinion of the investigator, there is...

...- Has centrally confirmed MSI-H/dMMR status...

...- Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H) OR...

...- Prior to Cycle 1 Day 1 (C1D1), documentation of tumor dMMR/MSI-H status must be available based on local testing....

...Consistent with high-frequency microsatellite instability MSI-H 2....

...- Participants' tumor must have an MSI-H or dMMR status according to institutional guidelines and/or according to the College of American Pathologists, determined at any time prior to enrolment....

...- Solid cancer that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:...

Pembrolizumab provided clinically meaningful antitumor activity and durable responses in pts of Chinese descent with MSI-H/dMMR tumors, with a manageable safety profile.

Median PFS was NR (95% CI: 15.8-NR) with an 18-mo PFS rate of 68.0%. The median OS was NR (95% CI: 9.5, NR) with an 18-mo OS rate of 80.2%....Pembrolizumab provided clinically meaningful antitumor activity and durable responses in pts of Chinese descent with MSI-H/dMMR tumors, with a manageable safety profile.

IMHOTEP is a prospective, multicenter, phase II study aimed to include 120 patients (pts) with localized resectable dMMR/MSI tumors, eligible for curative surgery….Focusing on the 54 operated pts, 31 and 23 pts received 1 and 2 neoadjuvant pembrolizumab doses respectively. The pCR rate was 38.9%....In this IMHOTEP interim analysis, we observed a limited complete pathologic response rate to short-course neoadjuvant pembrolizumab.

Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%....Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

The overall ORR was 34% (95% CI: 29.0 - 38.8 [11% CR; 23% PR). The ORR for the most common cancers enrolled were: endometrial 50%, gastric 39%, small intestine 58%, ovarian 32% and biliary tract 41%. The median DOR was 63.2 months (range, 1.9+ - 63.9+) for all cohorts with a 3 yr DOR rate of 69%. The median OS was 19.8 months (95% CI: 14.5, 25.8) with 3 yr OS rate of 39%. Median PFS was 4.0 months (95% CI: 2.4-4.3) with 3-yr PFS rate of 25%. Pembrolizumab continues to show robust antitumor activity and generates durable responses in pts with MSI-H or dMMR cancers regardless of tumor type, with a manageable safety profile.

Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor...Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population.

This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors...Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1)....Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation.

Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached).