Results

Merck’s Keytruda builds a commanding lead in frontline lung cancer with data from two more landmark trials

CHICAGO — Merck came to ASCO as the dominant industry player in frontline lung cancer. It’s going to leave ASCO with that rep intact — at the expense of its heavyweight rivals in the field still playing catch-up.

Roy Baynes

In two key studies out this morning, the pharma giant spelled out positive, critically important data underscoring Keytruda’s ability to fight a broad segment of the cases in the first-line lung cancer field as a monotherapy, with the Keytruda/chemo combo the best option (so far) in frontline squamous cases, where Roche tried — and largely failed — to elbow ahead this weekend.

“If you think of the whole frontline lung cancer field (except for EGFR and ALK mutation cases),” says Merck head of global clinical development Roy Baynes, “for pretty much everybody there is a Keytruda-based therapy that makes sense for those patients. It would be fair to say, all things being equal, the chemo combination is a very reasonable first-line option.”

But not everyone is going to be able to take the chemo combo, including patients with high co-morbidities. 

“Given the situation of all things being equal, the chemo combo would be a preferred therapy,” says Baynes. “And if there are circumstances where chemo is not a preferred therapy, monotherapy is a reasonable option.”

In its monotherapy study dubbed Keynote-042, patients in the Keytruda arm hit a median overall survival rate of 20 months, a clearly promising outcome compared to 12.2 months for chemo-solo patients with a PD-L1 tumor proportion score (TPS) of ≥50 percent. In patients with a TPS of less than 20%, the OS rate was reduced to 17.7 vs 13 months, and 16.7 vs 12.1 months for the overall study population of patients with a TPS of ≥1%.

The ‘042 study was the longer take of an earlier, faster trial numbered ‘024. And Merck views it as a more thorough confirmation of what it saw in that quick take.  

Then there’s Keynote-407, a combination of Keytruda and chemo for frontline squamous NSCLC  which had essentially the same design as Roche’s IMpower131, with Tecentriq. Merck’s team posted an impressive 36% reduction in the risk of death, a hazard ratio that won’t escape the attention of specialists. The Keytruda combination hit a median OS of 15.9 months compared to 11.3 months in the chemotherapy-alone group. The median PFS was 6.4 months for the Keytruda combination compared with 4.8 months for chemotherapy alone. 

And at the second interim readout, the ORR was 57.9% for the combo compared to 38.4% for the chemotherapy group. 

Roche has yet to see an OS advantage, but the PFS was close at 6.3 months for the Roche checkpoint vs 5.6 months for the control — just a 3 week advantage. As always when you compare data on drugs that were not in a head-to-head trial, it’s problematic to assess rival therapies. But without competitive OS results, Roche is left with a small advantage in PFS that won’t compare well for analysts covering the area.

The new data sets will also inevitably draw comparisons with Bristol-Myers Squibb’s work with Opdivo. Bristol-Myers has faced some stiff criticism for its setbacks as well as its trial designed in lung cancer, where they’ve been a consistent runner up to Merck.

The results build on the recently released data from Keynote-189 for nonsquamous non-small cell lung cancer, where researchers say that their combo of Keytruda and chemo clearly beat out chemo alone on overall survival, though the final OS rate for the combination has not yet been reached.

For Merck, it’s another chance to celebrate positive outcomes as rivals struggle to make their case for their drugs.

“As we look at the lung cancer arena,” Baynes adds, “we completed 5 randomized, controlled trials, with survival benefits in all 5. It’s quite remarkable.”

Not everyone is providing Merck with a standing ovation, though. Some practitioners in the field feel that those groups with a lower TPS score on PD-L1 are definitely not getting a tremendous amount of help from Keytruda. Here’s a note from lung cancer expert Jack West — a thoracic oncologist at the Swedish Cancer Institute at Swedish Medical Center — about my story:

Though I completely agree that results overall are impressive and that Merck is more or less running the table with pembro in advanced NSCLC, I need to highlight that the results are not as favorable as your language would syggest for the patients with low PD-L1 on KEYNOTE-042. The numbers you use for patients with lower tumor PD-L1 expression include the patients with high PD-L1, who prop up the results for the entire trial. When the results of the 042 trial are looked at for patients with PD-L1 1-49%, there is no efficacy advantage for pembro. This doesn’t mean that oncologists and patients won’t favor it for comparable efficacy and more favorable tolerability than chemo, but it’s important to clarify that the numbers you’re presenting for the “PD-L1 less than 20%” are actually not the numbers for that subset alone but the numbers for that subset combined with the larger number of patients with higher tumor PD-L1 expression. The results are pooled and merely don’t “de-select” the low PD-L1 group when they present “PD-L1 <50%” or “PD-L1 < 20%”, but they always include the patients with higher PD-L1 who are propping up the trial overall. And this is the subgroup for whomp pembro alone has been the standard of care for more than 18 months, for whom we’d already consider chemo alone an established inferior approach in the US and wouldn’t enroll on KN-042 these days.

Merck has been pouring billions of dollars into its Keytruda pipeline, and the investment has paid off handsomely with a blockbuster franchise and a collection of more than 750 trials — an explosion of clinical research. Five years ago, says Baynes, Merck was at ASCO with one presentation. For ASCO 2018, it’s presenting 140.


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