Merck & Co.’s Keytruda already has an accelerated FDA nod in refractory classical Hodgkin lymphoma. To prove it indeed deserves a place in the market, the PD-1 king has turned up a new head-to-head win. But even so, analysts aren't convinced it can unseat its rival.
Keytruda topped Seattle Genetics’ antibody-drug conjugate Adcetris at staving off cancer progression in a phase 3 trial among patients with relapsed or refractory cHL, an interim review by an independent data monitoring committee has found. The study has therefore hit one of its co-primary endpoints, Merck said Monday, with the more important analysis of the drug’s ability to prolong patients’ lives yet to yield results.
But analysts were quick to come to Adcetris' defense. Even though Keytruda beat out Adcetris alone in a late-line setting, SVB Leerink analyst Andrew Berens views Adcetris more as part of a cocktail. Data from a combo of Adcetris plus Bristol-Myers Squibb's rival PD-1 inhibitor Opdivo previously showed a response rate of more than 90%, which is “vastly superior to both drugs given as monotherapies, suggesting that Adcetris is unlikely to concede” the refractory/relapsing market to checkpoint inhibitor alone, he said in a Monday note.
BMS and Seattle Genetics are collaborating on the CheckMate 812 trial, testing Adcetris-Opdivo against Adcetris alone. It “may establish the combination as the regimen of choice,” Berens said.
J.P. Morgan's Cory Kasimov agreed, predicting in his own note that "Adcetris continues to gain traction in the front line (where MRK is notably absent) and is used in combination with PD-1s in the relapsed / refractory setting."
Keytruda’s current conditional green light is based on data from the phase 2 Keynote-087 trial. In 210 patients who had relapsed after autologous stem cell transplantation or Adcetris, the Merck drug meaningfully shrank tumors in 69% of them at a median follow-up of 9.4 months. In a recent two-year update, the objective response rate was 71.9%, lasting a median duration of 16.5 months. Merck launched the head-to-head Keynote-204 as a confirmatory trial for that indication.
While detailed numbers were not shared, Merck Research Laboratories’ vice president of oncology clinical research, Jonathan Cheng, said they mark a “statistically significant and clinically meaningful improvement in progression-free survival.” Merck plans to file these data with regulatory authorities as soon as possible, as they are “strongly supportive of Keytruda’s current indication in cHL,” he added.
As Cantor Fitzgerald analyst Louise Chen sees it, the positive results might prompt Merck to study Keytruda—including combinations—in newly diagnosed cHL or other blood cancers.
Keytruda hasn't always been successful in blood cancers, though. The FDA in 2017 stopped two phase 3 Keytruda studies in multiple myeloma after deaths emerged when testing the immuno-oncology drug with dexamethasone and either Celgene’s Pomalyst or Revlimid. According to results from interim analyses, as requested by the FDA on the Keynote-185 and Keynote-183 trials, the combos failed to improve clinical outcomes for patients.
Adcetris in 2018 became the first FDA-approved front-line regimen in over 40 years for stage III/IV cHL, Chen noted in a Monday dispatch to clients. However, based on conversations with industry experts, Chen’s team found that chemos are still widely used in new cHL patients because key opinion leaders “are not convinced of the strong efficacy advantage of Adcetris over chemo based on the trial data.”
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Traces of that slower-than-expected adoption showed in Adcetris’ fourth-quarter sales of $166.2 million in the U.S. and Canada, which came below the Street’s expectations of $174.5 million. And for 2020, Seattle Genetics is only expecting an organic sales increase in the single-digit percentages once the effect of a price increase is taken out, Berens recently noted. The company is playing the long game, counting on five-year front-line data to convince physicians.
As for Keytruda, Merck is conducting three registrational trials in cHL and primary mediastinal large B-cell lymphoma, for which it also has an accelerated approval that's awaiting verification from confirmatory studies. In addition, the New Jersey pharma just bought ArQule for $2.7 billion, a deal that centers on BTK inhibitor MK-1026 (ARQ 531) that’s part of a phase 2 dose expansion study for B-cell malignancies.
On top of that, Chen said further upside to industry expectations for Keytruda could come from triple-negative breast cancer, as well as use in the pre- or post-surgery settings to prevent cancer recurrence.
Recently, a Keytruda-chemo combo topped solo chemo at completely clearing signs of residual cancer in pre-surgery metastatic TNBC patients, with 64.8% of patients who got Keytruda achieving pathological complete responses, compared with 44.1% for those on chemo alone. Prior to that, Keytruda on its own had failed in a study of previously treated TNBC patients.