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Roger Dansey, head of Merck's clinical development in oncology, tells Scrip that the Keynote clinical program for the blockbuster PD-1 inhibitor continues to hit endpoints across diseases and there is much more to come.



research and development 



It is only three years ago that Merck & Co. Inc. got its first approval for Keytruda (pembrolizumab) in melanoma and data presented at the European Society for Medical Oncology congress in Madrid has highlighted how dominant the PD-1 inhibitor has become in such a short space of time.



Speaking to Scrip at the congress, Roger Dansey, head of the company’s clinical development in oncology, noted the huge amount of trials looking at Keytruda and possible combinations, pointing out that there are in excess in 500 studies listed on and the company itself is running over 40 registration trials. ESMO saw some new data being released on the Merck blockbuster and some important updates on previous studies.


One of the most important was an update on the Keynote-021 (cohort G) trial investigating Keytruda in combination with pemetrexed and carboplatin in previously untreated advanced non-squamous non-small cell lung cancer, with or without PD-L1 expression. With an additional five months of follow-up, median progression-free survival for Keytruda plus the aforementioned chemotherapies was 19.0 months, compared with 8.9 months for the chemo arm.



Dansey said the data were impressive and noted that the hazard ratio for overall survival improved to 0.59 in the ESMO update from 0.69 as reported from an earlier update at the American Society of Clinical Oncology meeting in June. "It suggests that this approach of giving Keytruda plus chemo upfront is really a winning approach in terms of tighter disease control and improving survival."



Analysts at Leerink approve of the approach, saying that Keynote-021G "may be able to serve as the confirmatory trial to convert this regimen's accelerated approval to full approval" in the US. They noted that overall response rate for the combo arm remains at 57% (versus 32% for chemo only) and importantly, the PFS benefit appears to be maintained beyond one year, with the rate dropping off by only 5% (57% to 52%) between 12 and 18 months - the chemo arm drops from 37% to 29% during the same period.



EU Okay For Bladder Cancer

Onto bladder cancer, where a couple of days before ESMO Merck got European approval for Keytruda for use as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemo. It also got the nod to be used in adults who are not eligible for cisplatin-containing chemo.



Dansey noted that the second, front-line approval, which was based on Phase II data from the Keynote-052 trial, is particularly striking. "We were very pleased and excited that the European Medicines Agency saw its way to approving a non-randomized trial," he said, adding that this is in a high unmet need group, patients aged of over 75-85 who cannot tolerate heavy chemo. "They may only have gone to palliative care and now Keytruda is now an option."



Another updated Keynote trial ("we are into the 700s now," Dansey quipped) was in stomach cancer. One cohort of the Keynote-059 trial showed a promising response rate in metastatic gastric cancer treated in the third line or beyond, prompting investigator Ian Chau of the Royal Marsden Hospital in London to say "the likelihood is that pembrolizumab will become a standard treatment option in this setting in the near future". It was filed for that indication in the US earlier this year.



Dansey also spoke about Keynote-040 in head and neck cancer: "The first trial actually where we have missed any statistical endpoint." However, the 19% improvement in overall survival only narrowly fell short "and showed there is a very clear biomarker effect with PD-L1”. Lead investigator Ezra Cohen, speaking at an ESMO press conference said that even though the study did not meet its primary endpoint, "I still think it is a positive trial. It reinforces that pembrolizumab should continue to be offered as an important option for all patients with this devastating disease." (Also see "Merck's Keytruda Gets Benefit Of Doubt, Despite Failing in Head & Neck" - Scrip, 24 Jul, 2017.)



It is clear that there is still much mileage left in the Keynote clinical program and Dansey told Scrip that "none of our studies have closed, not even the original one – we have a commitment, an interest and, I think, a responsibility, to report long-term outcomes for all of these trials."



Combo With Incyte's IDO1 Shows Promise


Dansey also expressed satisfaction with the results of a keenly watched Phase I/II trial in melanoma combining Keytruda with Incyte Corp.’s IDO1 enzyme inhibitor epacadostat. An updated analysis in Madrid showed that among all patients with advanced melanoma, including treatment-naïve and -experienced, the overall response rate was 56% (n=35/63) in patients treated with the combo. Median PFS was 12.4 months and a complete response was seen in nine patients.



Dansey said that if "IDO1 turns out to be an efficacious intervention, it's going to be a major advance because it is very safe." Unlike anti-CTLA-4 therapies, which "clearly carry some safety baggage," he noted that the adverse event with IDO1 is rash. "In general, you add something you expect something with a greater safety burden, so IDO1 has a very effective profile, both in terms of efficacy and safety."



The oncology chief noted that early-stage disease is a key focus for Merck and a neoadjuvant approach, saying that "as you move to earlier and earlier treatment, you have an immune system that is relatively intact that hasn't been beaten up by other therapy [and] that is the time to get the best treatment effect."



Some of the trials that Merck is running in the neo-adjuvant/adjuvant setting include Keynote -091, a Phase III study in patients with stage IB/II-IIIA NSCLC (estimated primary completion date is Aug. 2021), Keynote-054 in melanoma (May 2018), Keynote-522 for triple negative breast cancer (Nov 2018). Keynote-664 for renal cell carcinoma (Nov. 2022) and Keynote-585 for gastric cancer (July 2023).



When asked whether there are too many trials being conducted, looking at a jaw-dropping number of combinations, Dansey told Scrip that "Keytruda is foundational and there is every reason to believe that the PD-1 axis is pivotal and once you accept that, you have to build on that, it would make no sense not to leverage it with other combinations." He added that when Merck sees an attractive combination, be it IDO1 or oncolytic viruses, the firm is prepared to back studies but "at some point, there will have to be a funnel, it can't be never-ending development."



There will come a point where choices have to be made, he said, "Where you say, 'Yes, that looks good but in the environment you are in, it may not be good enough to beat the new standard.' However, we are not quite there yet."



Dansey concluded by saying that "late-stage development used to be an organized activity – Phase I, Phase II, relapse Phase III, front-line Phase III, adjuvant Phase III – a 10-15 year span. Now we are in three-year cycles where everything is running at once, in both the late-world and the early world of discovery. Everything is running in parallel without waiting for some sequential outcome, but the reason is because the results are amazing."

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