Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the European Commission has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy...

Merck...today announced that KEYTRUDA, Merck’s anti-PD-1 therapy, has received two new approvals from the Japan Pharmaceuticals and Medical Devices Agency (PMDA)....KEYTRUDA as a monotherapy is approved for the treatment of patients with unresectable, advanced or recurrent high microsatellite instability (MSI-H) colorectal cancer, based on results of the Phase 3 KEYNOTE-177 trial.

Merck...announced that Health Canada has approved KEYTRUDA (pembrolizumab), Merck's anti-PD-1 therapy, for the first-line treatment, as monotherapy, for adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).

Keytruda as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI H) or mismatch repair deficient (dMMR) colorectal cancer in adults.

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated…for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC)…Microsatellite Instability-High or Mismatch Repair Deficient Cancer…for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)…colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is recommended as an option for treating tumours with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency in adults with...colorectal cancer after fluoropyrimidine combination therapy, only if they cannot have nivolumab with ipilimumab.

In dMMR/MSI-H mCRC patients, the ICI pembrolizumab has demonstrated benefit over standard ChT and targeted agents, in the first-line setting and it is recommended as standard of care…

Treatment of Metastatic Colorectal Cancer...In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors...

MSD’s immunotherapy Keytruda has gained UK National Institute for Health and Care Excellence (NICE) backing as a first-line treatment for certain colorectal cancer patients...The PD-1 inhibitor has been recommended for NHS use for the treatment of adults with previously untreated metastatic colorectal cancers with high levels of microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR).

...the panel recommends pembrolizumab or nivolumab, alone or in combination with ipilimumab, as options for first-line treatment of MSI-H/dMMR mCRC only for patients who are not appropriate for intensive therapy.

Median OS was NR (range, 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65 [95% CI, 0.27-1.55]), and ORR was 50% (95% CI, 28-72) versus 46% (95% CI, 27-67)….These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC.

At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4–38·1) with pembrolizumab versus 8·2 months (6·1–10·2) with chemotherapy (HR 0·59, 95% CI 0·45–0·79). In this updated analysis, although pembrolizumab continued to show durable antitumour activity...findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

As 1L therapy for patients with MSI-H/dMMR mCRC, pembrolizumab vs chemotherapy provides statistically superior PFS...

A total of 307 pts with MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to 1L pembro 200 mg Q3W for up to 2y or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab....At final analysis, median PFS was 16.5 mo vs 8.2 mo (HR 0.59; 95% CI, 0.45-0.79)...Confirmed ORR was 45.1% (20 CR, 49 PR) vs 33.1% (6 CR, 45 PR). Median (range) DOR was NR (2.3+ to 53.5+) vs 10.6 mo (2.8 to 48.3+), respectively….As 1L therapy for pts with MSI-H/dMMR mCRC, pembro vs chemo provides statistically superior PFS...

Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed.

Merck...announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion recommending approval of KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. This recommendation is based on results from the pivotal Phase 3 KEYNOTE-177 trial, in which KEYTRUDA, as a monotherapy, demonstrated a significant improvement in progression-free survival compared to chemotherapy (investigator’s choice: mFOLFOX6 with or without bevacizumab or cetuximab; or FOLFIRI with or without bevacizumab or cetuximab), a current standard of care.

Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal cancer…

1L P compared with C showed clinically meaningful improvement in PFS, led to more durable responses and improved safety profile in the total pop of pts with dMMR/MSI-H mCRC.

A total of 307 pts with MSI-H/dMMR mCRC as determined locally and ECOG PS 0 or 1 were randomly assigned 1:1 to first-line pembro 200 mg Q3W for up to 2 years...Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P=0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) duration of response was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo.

...cohort B enrolled pts with metastatic CRC, MSI-H status confirmed locally by IHC or PCR...Eligible pts received pembrolizumab 200 mg...ORR was 32% (95% CI, 21-45) with 2 CRs and 18 PRs. Median DOR was not reached (NR); 95% of responses were ongoing with DOR ≥6 mo in 75% of responders. Median PFS was 4.1 month (95% CI, 2.1-NR) with a 12-month PFS rate of 41%.

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

......

...- 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)....

...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)....

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

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

...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...

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

...• 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. ...

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

Phase I-II bridge enrolled 8 patients with dMMR/MSI-H treatment-naïve mCRC...5/7 (71%, CI: 95% 29.0, 96.3) patients achieved objective response: 1 (14%) complete response (CR) and 4 (57%) partial responses (PR)...The combination of Nous-209 and pembrolizumab is safe, well tolerated and shows encouraging clinical efficacy in patients with treatment-naive dMMR/MSI-H mCRC eligible for anti-PD-1 therapy.

Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B….Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response....Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC.

Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months….This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice.

First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.

This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors...A total of 35 patients were enrolled, including 27 patients with colorectal cancer...Among 33 evaluable patients, best overall response rate was 82%.

...Merck...today announced the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of the following microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy; advanced or recurrent endometrial carcinoma who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation; unresectable or metastatic gastric, small intestine or biliary cancer who have disease progression on or following at least one prior therapy....The CHMP’s recommendation was based on results from the Phase 2 KEYNOTE-158 trial as well as results from the Phase 2 KEYNOTE-164 trial...

Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30-0.51) and 0.04 (95% CI 0.00-0.09), respectively. PD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC.

Pts received pembro 200 mg IV Q3W for ≤35 cycles or until disease progression, unacceptable toxicity, or withdrawal....ORR was 33% in cohort A and 35% in cohort B; median OS was 31.4 mo (95% CI, 21.4-58.0) and 47.0 mo (19.2-NR), respectively...Pembro continued to show durable clinical benefit, remarkable OS, and manageable safety in pts with previously treated MSI-H/dMMR mCRC.

...pembrolizumab is superior to the current standard of care, significantly improving progression-free survival when deployed up front to treat patients with metastatic DNA mismatch repair/microsatellite instability-high colorectal cancer.

Median follow-up was 15.6 months. The ORR was 36.8 % (95% CI, 29.3% to 42.8%). Median progression-free survival was 5.3 months (95% CI, 2.9 to 5.9 months) and median overall survival was 21.5 months (95% CI, 12.8 months to not reached)….Pembrolizumab monotherapy demonstrated durable clinical benefit and manageable safety in patients with metastatic MSI-H/dMMR colorectal cancer who had previously received 1 line of treatment.

ORR was 32.8% (3CR, 17PR; 95% CI% 21.3-46.0) for cohort A and 34.9% (8CR, 14PR; 95% CI 23.3-48.0) in cohort B. Median DOR was not reached (NR [range, 6.2-41.3+]) and not reached (range, 3.9+ to 37.1+), respectively. Fifteen pts in cohort A and 17 in cohort B had ongoing responses at data cutoff. Median PFS was 2.3 mo (95% CI 2.1-8.1) with 3-yr PFS rate of 31% in cohort A and was 4.1 mo (2.1-18.9) with 3-yr PFS rate of 34% in cohort B. Median OS was 31.4 mo (21.4-NR) with 3-yr OS rate of 49% in cohort A and was not reached (19.2-NR) with 3-yr OS rate of 52% in cohort B. Nine pts (6 in cohort A, 3 in cohort B) had a second course of treatment. The best response in second course was PR in 1 patient each in cohort A and B.

129 MSI-H pts across 33 tumor types received first P after May 2017. CRC (N=36) and Endometrial cancer (N=39) were most common....P use was observed across 33 MSI-H tumor types. Median OS exceeded 1 yr across all pts and in CRC, Endometrial, and Other cohorts. 1 yr OS rate was consistent with P trial outcomes.

Our study is the one of the largest reported analysis of LS associated cancer patients treated with ICIs and included LS patients with both MSI and MSS tumors...This encouraging response in MSS tumors along with higher response rates in LS associated cancers as compared to non-LS MSI tumors, suggests that there may be additional drivers of response to ICI in LS patients leading to superior responses.

A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months).

...a 75-year-old woman diagnosed with ascending colon cancer...Lymph node biopsy confirmed MSI-High, and pembrolizumab therapy was initiated as the fourth-line treatment. After the therapy, the lymph nodes reduced markedly.