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Merck's KEYNOTE-061 gastric cancer study is the latest example of a checkpoint inhibitor failing in Phase III after accelerated approval.






The failure of Merck & Co. Inc.'s Phase III KEYNOTE-061 study of Keytruda in second-line advanced gastric cancer may wind up having little commercial downside, as there will be no change in labeling.



The KEYNOTE-061 study tested Keytruda (pembrolizumab) as a monotherapy against paclitaxel chemotherapy in the treatment of 592 patients with advanced gastric or gastroesophageal junction adenocarcinoma, following first-line platinum and fluoropyrimidine chemotherapy.



Keytruda failed to show a significant improvement in overall survival in patients testing positive for PD-L1 expression – the primary endpoint – although there was a trend in the right direction (the hazard ratio was 0.82, the p-value was 0.042 and the confidence interval was 0.66-1.03). There was also no significant improvement in progression-free survival (PFS), the company reported Dec. 14. No new safety signals were identified.



Keytruda received accelerated approval from the US FDA in third-line PD-L1-positive advanced/metastatic gastric cancer (for use after fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy) in September. The filing was supported by response rate data from a single-arm Phase II study. (Also see "FDA Approval Round Up: Keytruda, Opdivo Add Claims" - Pink Sheet, 24 Sep, 2017.)



FDA's approval letter guided the company to conduct and submit the results of "one or more randomized trials to verify and describe the clinical benefit of pembrolizumab over standard therapy based on a clinically meaningful improvement in overall survival in patients with PD-L1 positive, microsatellite stable/mismatch repair (MMR) proficient metastatic gastric or gastroesophageal junction adenocarcinoma."



Merck said in its statement about the KEYNOTE-061 failure that "the current indication remains unchanged" and that it continues to evaluate Keytruda in two Phase III studies. The KEYNOTE-062 study tests Keytruda as a monotherapy or in combination with chemotherapy against chemotherapy alone in PD-L1+ advanced gastric or gastroesophageal junction cancer; KEYNOTE-585 is evaluating Keytruda with chemotherapy against chemotherapy in the neoadjuvant/adjuvant setting.



The company confirmed to Scrip that it already has discussed the KEYNOTE-061 study with FDA and does not expect any changes to the gastric cancer indication at this time.



Either KEYNOTE-061 or KEYNOTE-062, which is expected to read out in February 2019, were positioned to serve as a confirmatory study for the third-line approval in September.



BMO Capital Markets analyst Alex Arfaei said in a Dec. 14 note that the studies of Keytruda in earlier lines of therapy "have a better chance of showing an OS benefit."



"This is based on KN-061's narrow OS miss, and the fact that the OS benefit seen with IO therapies typically increases in earlier disease. Moreover, KN-062 is in an all PD-L1+ patient population, and perhaps Merck will select a higher PD-L1 threshold for the primary endpoint analysis based on findings from KN-061," the analyst said.



Gastric cancer is a small indication for PD-1/L1 inhibitors relative to other tumor types, but collectively the modest market approvals add up and the major sponsors of checkpoint inhibitors have been active in developing their drugs for this disease.



Bristol-Myers Squibb Co./Ono Pharmaceutical Co. Ltd.'s PD-1 inhibitor Opdivo (nivolumab) demonstrated a modest improvement in overall survival in the Phase III ONO-4538-12 study, which tested the drug against placebo in patients with advanced gastric cancer refractory to or intolerant of standard therapy.



Merck KGAA and partner Pfizer Inc.announced in November that their PD-L1 inhibitor Bavencio(avelumab) failed to improve overall survival compared to chemotherapy in the Phase III JAVELIN Gastric 300 study of third-line advanced gastric cancer. (Also see "Pfizer/Merck KGAA's Bavencio Gastric Cancer Failure Not As Bad As It Seems" - Scrip, 28 Nov, 2017.)



While the results of KEYNOTE-061 are unfortunate, expectations were low given the recent failure of avelumab in third-line gastric cancer, BMO Capital Markets' Arfaei said. "Further, gastric cancer is a relatively small market," he added.



Meanwhile, investors remain focused on the larger non-small cell lung cancer (NSCLC) market. Results for Keytruda in the KEYNOTE-042 NSCLC study are due in the first quarter of 2018 and could broaden the drug's monotherapy label, Arfaei noted.



KEYNOTE-042 tests Keytruda against platinum-based chemotherapy in PD-L1+ advanced or metastatic NSCLC.



Just The Latest Phase III Failure



The failure of the KEYNOTE-061 gastric cancer study may reinforce clinical concerns in some quarters about early approvals of checkpoint inhibitors based on surrogate measures.



The KEYNOTE-061 gastric cancer is the not the first time Keytruda has failed in an earlier line of treatment after being approved in a later line, nor is it the only PD-1/L1 inhibitor to do so.



Keytruda received accelerated approval for recurrent or metastatic head and neck cancer in August 2016, a filling supported by response rate data in the single arm KEYNOTE-012 study. However, in July of this year the company announced the failure of Keytruda to show a significant survival benefit in the Phase III KEYNOTE-040 head and neck cancer study, which tested Keytruda against investigator's choice of chemotherapy. As with gastric cancer, the company said it did not expect a label change, despite the trial's failure. (Also see "Merck's Keytruda Gets Benefit Of Doubt, Despite Failing in Head & Neck" - Scrip, 24 Jul, 2017.)



Accelerated approval of Roche's PD-L1 inhibitor Tecentriq (atezolizumab) in bladder cancer in May 2016 was followed by the drug's failure in May of this year to demonstrate an improvement in overall survival over chemotherapy in the Phase III IMVigor211 confirmatory study in the second-line setting. (Also see "Bladder Cancer Market Wide Open As Tecentriq Fails Confirmatory 2L Trial" - Scrip, 10 May, 2017.)



At the time, Roche explained that the performance of the chemotherapy arm was better than expected. Tecentriq has maintained its approval in the indication.


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