Merck Stresses Overall Survival In Keytruda/Chemo '189 Trial Revamp

Merck is changing the statistical analysis of combination study in first-line lung cancer to include dual endpoints of progression-free-survival and overall survival, and has withdrawn a filing for the combination in Europe based on mid-stage data.

Any change to the design of the immuno-oncology combination trials in lung cancer attracts enormous attention. Just one day after Bristol-Myers Squibb Co. was grilled over the CheckMate 227 study of its PD-1 inhibitor Opdivo (nivolumab) with the CTLA-4 inhibitor Yervoy in non-small cell lung cancer, Merck & Co. Inc. came under fierce questioning as it announced a delay and endpoint change to the eagerly awaited KEYNOTE-189 study of its PD-1 inhibitor Keytruda (pembrolizumab) with chemotherapy in first-line NSCLC.

For Bristol, CheckMate 227 is its final big shot at the first-line non-small cell lung cancer market, and investors and analysts on the firm's Oct. 26 earnings call were keen to understand whether Bristol could use the emerging tumor mutation burden biomarker to help find responders. Bristol execs declined to comment on whether the statistical plan for CheckMate 227 has been altered. (Also see "Bristol's Opdivo Delivers, But CheckMate 227 Uncertainties Cloud Quarter" - Scrip, 26 Oct, 2017.)

Emphasis On Overall Survival

Keytruda has accelerated approval for use in combination with Eli Lilly & Co.'s Alimta (pemetrexed) and carboplatin chemotherapy in first-line non-small cell lung cancer (NSCLC) in the US, based on results from the KEYNOTE-021 Cohort G study. KEYNOTE-189 is a confirmatory study that previously had progression-free survival (PFS) as a primary endpoint and overall survival as a secondary endpoint. These are now dual co-primary endpoints, the company said as part of its third-quarter earnings report on Oct. 27.

"This revision has been reviewed and accepted by the FDA. The timeline for completion of KEYNOTE-189 has therefore been extended to capture longer-term survival data, with an estimated completion date depending upon the underlying event rate in February of 2019. The study is fully enrolled as we announced in the second quarter, and the opportunity exists to conduct interim analyses again depending upon the underlying event rates that we observe," Roger Perlmutter, president of Merck Research Laboratories, said during the earnings call. The trial had been expected to have an assessment at the end of 2017.

The company also announced at the close of business on Oct. 27 that an application for Keytruda with Alimta and carboplatin in first-line treatment of metastatic non-small cell lung cancer, based on the 021G trial, has been withdrawn in Europe.

"Merck is confident in the clinical data from this rigorously conducted trial, which demonstrated significant improvements in overall response rate (ORR) and progression-free survival (PFS) for the Keytruda combination regimen compared to chemotherapy alone. Additionally, the company’s broad clinical development program includes a number of studies evaluating Keytruda in combination with chemotherapy in the first-line NSCLC setting. Merck looks forward to sharing data from these studies with regulatory authorities and the medical community as they become available," the company said in a statement.

Merck's filing for the chemo combo in Europe based on the 021G data "was a long shot – it would be highly unusual for European regulators to approve an application like this based on Phase II data," Bernstein analyst Tim Anderson said in an Oct. 27 note, adding that "the bar to FDA approval in oncology is lower, and the US approval is very highly likely NOT in jeopardy."

The 021G study had only 16 patients per arm. With the improved power of the '189 study, the company will be following event rates very closely and is hoping to see a meaningful separation in overall survival curves, Perlmutter said.

The company aims to preserve the overall survival results in the '189 study. Those who don't respond will have the option of crossing over to treatment that includes Keytruda. There will be opportunities for interim analyses but the company is going to be "careful to preserve the integrity of the study," Perlmutter said.

BMO Capital Markets analyst Alex Arfaei commented in an Oct. 27 note that the KEYNOTE-189 update is positive in that the company added overall survival to the primary endpoint. KEYNOTE-189 is probably "Merck's best chance at hitting overall survival as the PD-1s become the standard of care in second-line non-small cell lung cancer," Arfaei said.

Perlmutter acknowledged that in the '189 study, everybody in the comparator chemotherapy arm is permitted to get Keytruda after treatment failure.

"And what that means is you either got Keytruda at the beginning or you got it late, and because there's such a dramatic decline in PFS, with a median PFS of less than nine months in the chemotherapy arm, everybody gets Keytruda pretty quickly," Perlmutter said.

Allowing patients to cross over, however, can make it harder to show a survival benefit.

How Keytruda performs as an early versus late treatment is very important and the company wants to make sure it understands this and obtains solid data in the '189 study, because ultimately "that's practice-changing," Perlmutter said.

Keytruda Sales Almost Double

Keytruda was a bright spot for the company, as global human health sales declined by 4% to $9.2bn, due to the loss of exclusivity of several products. But Adam Schechter, executive vice president and president of global human health at Merck, exec said that the company continues to see "strong underlying growth" from launched products, including Keytruda, Zepatier (elbasvir/grazoprevir) and Bridion (sugammadex) (see box).

Keytruda posted about $1bn in sales during the third quarter – almost 200% growth, aided by increased use in first-line lung cancer, Morningstar analyst Damien Conover pointed out in an Oct. 27 note, although this was shy of analyst expectations. Opdivo reported sales of about $1.3bn for the third quarter, up 38% from the same period in 2016.

"Nearly one in three new lung cancer patients in the US are being started on Keytruda, making it the most prescribed treatment for new metastatic lung cancer patients," Merck's Schechter said.

"Although there was some noise in the channel this quarter as distributors normalized their inventory levels, if you look at the most recent script data, we have seen substantial growth in demand both year-over-year as well as quarter-over-quarter. We continue to build on our leadership position in lung cancer, with growth driven by continued adoption of Keytruda monotherapy in high expressers as well as the uptake of the Keytruda-Alimta combination in the first-line setting. Across all of lung cancer, nearly one in three new lung cancer patients in the US are being started on Keytruda, making it the most prescribed treatment for new metastatic lung cancer patients," Schechter said.

Lung cancer was the largest tumor type for Keytruda, but indications outside of lung cancer contributed to about 45% of US sales – in addition to continued leadership positions in melanoma and head and neck cancer, the company has seen strong momentum a launch in bladder cancer launch, Schechter said. Within just two months of launch in second-line or greater treatment of bladder cancer, Keytruda achieved leadership among immuno-oncology drugs in terms of share of new prescriptions, even though it was the fifth market entrant, Schechter said.

Merck's Q3 2017 Highlights, Sales Vs. Consensus Expectations

Keytruda (pembrolizumab): $1,047m vs. $1,066m

Zepatier (hepatitis C virus combo) $468m vs. $544m

Januvia/ Janumet (sitagliptin/metformin): $1,525m vs. $1,489m

Zetia (ezetimibe): $320m vs. $317m

Vytorin (ezetimibe/simvastatin): $142m vs. $171m

Remicade (infliximab): $214m vs. $191m

Gardasil (human Papillomavirus 9-valent vaccine, recombinant): $675m vs. $776m

Isentress (raltegravir): $310m vs. $304m

Source: Jeffrey Holford, Jefferies

Merck was also asked during the call about its philosophy in IO trials regarding tumor mutation or mutational burden (TMB), as a high mutation burden is thought to be associated with better response to treatment.

The company has done a lot of work on TMB but has not included this biomarker in the '189 study as an explicit endpoint in part because it does not have data to show at what point in each tumor type TMB rises to the point where its meaningful, Perlmutter said.

The company has a lot of data from looking at patients across tumor types with microsatellite high (MSI-high) cancer, and it can see the magnitude of tumor mutational burden in that population where response rates are quite good, and can look at TMB in other populations.

"But there's still work to be done to define what those cut points actually are. So that's not part of the '189 program," Perlmutter said.