Merck Poised To Be First To Market With A PD-1 For First-Line Lung Cancer

Merck’s Keytruda improved progression-free survival and overall survival in previously untreated non-small cell lung cancer patients in the highly-anticipated KEYNOTE-024 trial, all but guaranteeing a rapid FDA approval in the indication.

Positive progression-free survival and overall survival data from Merck & Co. Inc.’s high profile KEYNOTE-024 trial testing Keytruda (pembrolizumab) in patients with previously untreated advanced non-small cell lung cancer (NSCLC) positions Keytruda to beat Bristol-Myers Squibb Co.’s Opdivo (nivolumab) to a first-line lung cancer indication.

The winner long-term in the high stakes market remains very much up in the air, however, as the details of the trial were not released. Bristol’s trial in a similar patient population, CheckMate 026, is still ongoing, with data anticipated in the third quarter, and there is still a big question about the optimal threshold for testing tumors for PD-L1 expression. Both KEYNOTE-024 and CheckMate 026 used a different threshold for enrolling patients by PD-L1 expression, which could impact the results.

What does seem apparent is that Merck is on a fast track toward having Keytruda approved for first-line lung cancer. In an interview June 15, the day before the data were announced, Head of Global Clinical Development, Merck Research Laboratories Roy Baynes said the company will move as quickly as possible to get the data filed with FDA.

Keytruda, like Bristol’s Opdivo, is already approved for the second-line treatment of lung cancer and FDA will likely move quickly to approve the drug for first-line use as it has done in other indications for the PD-1 inhibitors (Also see "How Fast Do PD-1s Get To Market?" - Pink Sheet, 30 Nov, 2015.).

BMO Capital Markets analyst Alex Arfaei predicted an ultra-speedy review within one month after filing. “We estimate that Keytruda could launch in the US market in 1L NSCLC in August,” he said in a same-day research note.

Merck plans to disclose the full data from KEYNOTE-024 at an upcoming medical meeting, expected to be the European Society for Medical Oncology (ESMO) meeting in October. The trial enrolled patients whose tumors expressed high levels of PD-L1 (tumor proportion score of 50% or more) and showed Keytruda was superior to chemotherapy for both the primary endpoint of progression-free survival and the secondary endpoint of overall survival.

Demonstrating the overall survival benefit in particular is a positive for Merck at such an early time point. An independent data monitoring committee recommended the trial be halted and that patients receiving chemotherapy be offered Keytruda.

Bristol – And Combinations – Right On Merck’s Heels

Merck’s lead in the first-line NSCLC market isn’t expected to be long-lasting. Bristol’s CheckMate 026 trial is on track to read out in the third quarter, pitting the two rivals against each other in a fierce competition for market share in what is believed to be the largest single market for PD-/L1 inhibitors.

“The timing advantage Merck has over Bristol is not likely very material under the assumption that both sets of results get presented in full at the same meeting,” Bernstein analyst Tim Anderson said. “Rather, what will matter more is how the two sets of findings compare side by side.”

Opdivo has thus far dominated in the second-line lung cancer market because it was cleared by FDA without a requirement for PD-L1 testing, unlike Keytruda, leading patients and physicians to choose the more convenient option. Only about 30% of lung cancer patients are being tested for PD-L1 expression, with the majority of those being in the first line, according to Merck, but the firm has played up that Keytruda captures the majority of patients tested (Also see "Merck Is Finding PD-L1 Testing Is Helping Keytruda" - Pink Sheet, 5 May, 2016.). Most of Keytruda’s sales have been coming from use in melanoma.

The dynamics will be different in the first-line lung cancer market because both drugs are expected to be approved with a requirement for PD-L1 testing. Having the experience in the market with testing could be an advantage for Merck.

Merck and Bristol have deployed different strategies in clinical trials when it comes to testing for the biomarker, however. It remains to be seen where the advantage will lie or if there is one at all.

KEYNOTE-024 enrolled only the highest expressers of PD-L1, 50% or greater, while CheckMate 026 enrolled patients with a PD-L1 expression of 1% or greater. Although PD-L1 is an imperfect biomarker, high expressers have been shown in clinical studies to generally respond more favorably to treatment with a PD-1 blocker.

The design of the trials could yield different outcomes – or indications if FDA should choose to limit the use of Keytruda to patients with a PD-L1 expression of 50% or more. That limited marketed represents only about 25-30% of NSCLC patients, according to analysts.

But BMO’s Arfaei predicted FDA won’t restrict the label. “Based on the good data from KEYNOTE-001, which in Rx naïve patients with 1-49% PD-L1 expression showed median OS of 19.5 months, and the FDA’s unwillingness to restrict the Keytruda 2L+ label to a specific PD-L1 threshold from the single arm KN-001 trial, and the growing body of evidence illustrating the dynamic nature of PD-L1 expression, we believe that Keytruda will likely get an unrestricted 1L label, similar to the wording of its current indication,” he said.

Labeling for Keytruda currently recommends it for use in PD-L1 positive patients as determined by an FDA-approved test. The clinical studies section reflects data for patients with at least 50% expression of PD-L1, but Merck had submitted a supplemental new drug application (sNDA) to include data from KEYNOTE-001 with expression levels of just 1% or higher (Also see "Keeping Track: Personalized Medicine For Lung Cancer Evolves; Idelvion Is CBER's First Novel Approval In 2016" - Pink Sheet, 14 Mar, 2016.).

Merck’s Baynes stood by the company’s PD-L1 strategy despite the fact the company has given up significant share to Bristol, pointing to the data that has come out of the second-line NSCLC trials.

“We know that patients who are PD-L1 negative do not do as well as patients who are PD-L1 positive. In some of the data sets, patients who are PD-L1 negative might actually do worse than standard chemotherapy,” he said. “In contrast, patients who are strongly PD-L1 positive have very much higher response rates, durable response rates and indeed impressive PFS and OS curves.”

The even bigger battle for the lung cancer market will come further out if and when more PD-1/L1 drugs join the market. Roche’s Tecentriq (atezolizumab) was approved for metastatic urothelial carcinoma May 18 (Also see "Atezolizumab At Last: Roche Makes Its Immuno-Oncology Debut" - Pink Sheet, 18 May, 2016.). Roche has a filing for second-line NSCLC pending at FDA, and expects to have Phase III data on Tecentriq and chemotherapy in combination next year (Also see "For Roche Immuno-Oncology, It’s Steady As She Goes" - Pink Sheet, 13 Jun, 2016.). Bristol, meanwhile, is exploring the combination of Opdivo with the CTLA-4 inhibitor Yervoy (ipilimumab) in lung cancer (Also see "What's Next For Bristol's Opdivo/Yervoy Combination" - Pink Sheet, 6 Jun, 2016.).

BMO Capital Markets forecast that lung cancer will be the single biggest opportunity for Keytruda, with sales of $300m coming from the indication in 2016, growing to $3.5bn by 2020.