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Executive Summary

Merck’s strong Phase II data testing Keytruda with chemotherapy in first-line lung cancer may put pressure on future IO/IO combinations when it comes to toxicity, efficacy and – importantly – cost.


Scrip | Pharma intelligence


Merck & Co. Inc. presented the first positive Phase II data comparing the PD-1 inhibitor Keytruda (pembrolizumab) in combination with chemotherapy versus chemotherapy alone at the European Society for Medical Oncology (ESMO) meeting Oct. 9 and the data could raise the bar for future immuno-oncology combinations.

While the data are early, the positive results seen in the KEYNOTE-021 study suggest the combination of Keytruda with chemotherapy could become a new standard for treating first-line non-small cell lung cancer patients who test negative for PD-L1. The regimen also could be an option for some PD-L1 positive NSCLC patients.

The lower cost of an IO/chemo combination will raise the bar for IO/IO combinations.

The chemo combo data could have implications long-term in a critical area of drug development. If PD-1/L1 inhibitors prove to be an effective treatment in combination with chemotherapy, the regimen could put more pressure on the IO/IO combinations in which manufacturers are investing heavily. Both IO/IO and IO/chemo combos carry significant toxicities, but the cost of an IO/IO combo would most likely be much higher.

As Bernstein research analyst Tim Anderson pointed out in a same-day research note on the Keytruda/chemo data, “Yes, the combination brings with it all the toxicity of standard chemotherapy – but that is what patients are getting today anyway. Compared to alternative combinations involving branded IO drugs, the cost would be less, putting pressure on those manufactures of IO/IO combinations to fully substantiate their value to cost-minded payers,” he said.

Merck will ultimately need to confirm the positive results seen in KEYNOTE-021 with overall survival data in Phase III studies. Two Phase III trials testing different chemotherapy combinations are ongoing with results expected in the second half of 2017. One of the studies, KEYNOTE-189, follows a similar design as KEYNOTE-021, while the other is testing Keytruda in combination with carboplatin and paclitaxel or nab-paclitaxel in patients with squamous NSCLC.

The KEYNOTE-021 results were overshadowed at ESMO by the surprising news that Bristol-Myers Squibb Co.’s rival – and market-leading – PD-1 inhibitor Opdivo (nivolumab) almost inexplicably failed to show a benefit in first-line NSCLC patients even among those stratified to a high PD-L1 threshold, while Merck has released positive overall survival data for Keytruda in the patient population, changing the dynamics of a market that many investors expected to unfold in Bristol’s favor.

Bristol previously released disappointing Phase III data in first-line lung cancer in patients with lower levels of PD-L1 expression. (Also see "Does CheckMate 026 Take Bristol Out Of The End Game?" - Scrip, 5 Aug, 2016.) But many of the company’s investors were holding out hope the results would be different in patients with a high PD-L1 status, as the data with Keytruda have shown in first-line lung cancer. (Also see "Merck Poised To Be First To Market With A PD-1 For First-Line Lung Cancer" - Scrip, 16 Jun, 2016.) However, Bristol revealed at ESMO that Opdivo didn’t even show a benefit in NSCLC patients with a high PD-L1 status. Meanwhile, Merck presented the full positive data in first-line lung cancer from KEYNOTE-024 at the meeting.

Positive Response Rates Regardless Of PD-L1 Status

KEYNOTE-021 enrolled 123 chemotherapy-naïve non-squamous NSCLC patients who were randomly assigned to receive Keytruda in combination with carboplatin plus Eli Lilly & Co.’s Alimta (pemetrexed) or the chemotherapy regimen alone. Patients were stratified by PD-L1 score: less than 1% or greater than or equal to 1%.

Those treated with the Keytruda regimen achieved a 55% objective response rare (ORR) compared to a 29% ORR for those treated with chemotherapy alone, the standard of care. The Keytruda combination also reduced the risk of disease progression or death by 47%.


Median PFS for the combo arm was 13 months versus 8.9 months for chemo alone. 


 Median progression-free survival on the combo arm was 13 months versus 8.9 months on the chemo arm, Merck reported. No meaningful difference in overall survival was seen yet, but Merck said the combination appeared to be encouraging and the data will continue to be reviewed until it is mature.

Grade 3 and 4 toxicities were seen in 39% of the combo arm versus 26% of the chemo alone arm, but they led to discontinuation in the same percentage of patients. One death related to treatment was reported on the combo arm versus two on the chemo arm.

The study, though early, could immediately result in some use of the combination in PD-L1 negative patients, who currently have limited treatment options. Management suggested the data could support compendia recommendations, though the company declined to disclose its regulatory strategy for the chemo combination.

“The good news is the data are readily available already for them now that it’s published in The Lancet,” President-Global Human Health Adam Schechter said during an investor presentation at the conference. The data were published simultaneously in The Lancet Oncology. “We’re hopeful that based upon the results that patients will have the opportunity to benefit from the chemo-Keytruda combination, and we’ll see what the compendia folks decide,” he added.


An Opportunity Opens For Chemo Combo In First-Line NSCLC

The data raise some questions about when chemotherapy should be used in combination with Keytruda in first-line lung cancer patients.

Merck Research Laboratories President Roger Perlmutter speculated the decision will be made on a case-by-case basis. “For example, a patient comes in and they have a non-squamous tumor and they have a proportion score that’s high and they could receive monotherapy, and you’re asking yourself as a physician and in discussion with your patient, should that person receive chemotherapy as well. That will be influenced a lot by the state of health of that individual,” Perlmutter said.

“You are going to look very differently at a patient that has a lot of comorbidities and whom adverse effects would be problematic. You wouldn’t want to give chemotherapy then to that person if you thought, gee, I can get a pretty good result with monotherapy with Keytruda, which is better tolerated. However, on the other hand, in a person who has no such comorbidities, maybe a younger individual, who is found incidentally to have advanced non-small cell lung cancer, you might treat that patient with a combination, I suspect.”

The advancement of the chemo combo regimen could have immediate implications for PD-1/L1 in combination with CTLA-4, the IO/IO strategy Bristol and others have been pursuing.

Bristol has been focusing on a combination of Opdivo with its CTLA-4 inhibitor Yervoy (ipilimumab), a pairing approved in melanoma and being tested in a first-line lung cancer trial expected to read out in 2018. AstraZeneca also is pursuing a similar strategy with its investigational PD-L1 inhibitor durvalumab in combination with its CTLA-4 inhibitor tremelimumab, while Roche, like Merck, is focusing on the development of its PD-L1 inhibitor Tecentriq (atezoliumab) in combination with chemotherapy. Almost every immuno-oncology player is looking even further to future IO/IO combinations.


IO/chemo and IO/IO regimens may eventually split the PD-L1-low market, Leerink's Fernandez said 


Leerink analyst Seamus Fernandez speculated in an Oct. 10 research note that IO/chemo and IO/IO regimens could eventually split the PD-L1-low market, including patients with PD-L1 status ranging from 1% to 49%, while IO/IO combinations will be used less in PD-L1 negative patients (those under the 1% threshold), with IO/IO combinations used in the highest PD-L1 expressers (those over 50%).

“We see a reasonable likelihood that both of these combos will be successful and find use in a substantial segment of the 1L NSCLC population,” Fernandez said. “We believe Bristol still has a significant opportunity to compete with Merck’s Keytruda in the PD-L1 high proportion of the market should the CheckMate-568 study repeat the benefits in CheckMate-012.”

The ’568 study is a single-arm Phase II trial testing the Opdivo/Yervoy combination in first-line NSCLC that is expected to read out in 2017, while the ’012 study is a Phase Ib trial of the combo that already reported out. Bristol is also running a pivotal CheckMate-227 study testing Opdivo/Yervoy in first-line NSCLC. (Also see "What's Next For Bristol's Opdivo/Yervoy Combination" - Pink Sheet, 6 Jun, 2016.)

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