With immuno-oncology (IO) revving faster than even optimists predicted and chemotherapy for non-small-cell lung cancer (NSCLC) fated to become an image in the rearview mirror, research continues to grope for the just-right levels of programmed death-ligand 1 (PD-L1) expression that lets programmed cell death-1 (PD-1) inhibitors work best.

Merck & Co. Inc.'s favorable outcome – "an unexpected and positive surprise," noted Leerink analyst Seamus Fernandez – from the phase III Keynote-24 trial investigating Keytruda (pembrolizumab) in previously untreated advanced NSCLC renewed buzz about the drug's chances against Bristol-Myers Squibb Co.'s (BMS) Opdivo (nivolumab), undergoing a similar trial in NSCLC called Checkmate-26. Last year, the FDA granted accelerated approval for Keytruda in patients whose PD-L1-positive NSCLC has advanced despite treatment, paving the way for such therapies in the U.S. Opdivo, first cleared in 2014, is approved for advanced melanoma, NSCLC that has advanced despite therapy, advanced renal cell carcinoma and classical Hodgkin lymphoma. (See BioWorld Today, Sept. 5, 2015.)

Kenilworth, N.J.-based Merck was the first to file a biologics license application for a drug targeting PD-1 or PD-L1, ahead of closest competitor BMS, though the latter's drug crossed the finish line first in Japan, where it's partnered with Ono Pharmaceutical Co. Ltd., of Osaka, Japan. (See BioWorld Today, May 7, 2014, and July 9, 2014.)

In Keynote-24, Keytruda was tried in patients whose tumors expressed high levels of PD-L1 (i.e., with a tumor proportion score of 50 percent or more), and the study met its primary endpoint by turning up superior data compared to chemo in progression-free survival (PFS) as well as the secondary endpoint of overall survival (OS). An independent data monitoring committee recommended that the trial be stopped and that patients on chemo be offered Keytruda instead.

"Merck confirmed to us that 'all hands are on deck' for getting this filed" for approval, Fernandez wrote in a research report. "BMS' shares, while under some modest pressure this morning, are holding up well," and the company confirmed to him that results from the Opdivo Checkmate-26 trial are due later this summer. BMS (NYSE:BMY) closed Thursday at $71.73, down 84 cents.

"Given [the company's] early initiation of Checkmate-26 and rapid recruitment, together with the longer treatment duration, our confidence that it can show an OS benefit in its broader group of PD-L1-high patients goes up," he wrote. "That said, Merck's data clearly raise the bar for identifying the 'sweet spot' for PD-L1 expression and [the] preferred use of PD-1 monotherapy over chemotherapy."

The data do more than that, lifting hopes for IO players across the board, such as Basel, Switzerland-based Roche AG and Astrazeneca plc, of London.

Merck's glory may not last. "As expected, we gained little information on the performance of Keytruda in this headline read-out," said Jefferies analyst Jeffrey Holford in a report. "We assume for now that we will not get further details on either the numerical response rate, PFS or OS benefit until the data are presented in full, presumably at the European Society for Medical Oncology meeting," which takes place in October. His firm has "set a hurdle of at least 8.4 months for median PFS, using data from Opdivo monotherapy in a similar patient subset as a benchmark." Holford predicted "the market will give Merck little credit after the initial reaction today," as data loom from BMS' Checkmate-26 in the broader patient population. Specifically, New York-based BMS is recruiting patients with low-medium levels of PD-L1 expression, probably around 5 percent to 10 percent as compared to Merck's 50 percent. Shares of Merck (NYSE:MRK) closed Thursday at $57.50, up $1.41.


BMS "has shortened the time gap in terms of time until they expect top-line data, so we think the advantage for Merck on that front is somewhat overstated," said Credit Suisse analyst Vamil Divan in a report. "Numerous experts we have spoken to in recent months believe Opdivo is likely to show positive results in Checkmate-26, so we remain confident." Furthermore, BMS could have a long-term advantage in first-line NSCLC with its combination approach of Opdivo plus BMS' approved melanoma drug Yervoy (ipilimumab), supported by the strong data that rolled out at the American Society of Clinical Oncology (ASCO) meeting recently, in Divan's view.

In NSCLC, the PD-1/PD-L1 agents likely will overtake chemo as an option, and the IO market could reach $35 billion by 2026, in the view of Leerink's Fernandez. His firm's 21-page report in January on the space cited major changes affecting the market model, including "lower average treatment durations in lung, kidney and bladder cancers, based purely on data in second-line and third-line disease – which may be conservative, and lower reported first-line treatment rates in lung cancer, partially offset by higher treatment rates in melanoma." Leerink increased its forecasts for BMS, "assuming a wider lead driven by faster-than-expected uptake of Opdivo, a recovery in Yervoy" and prospects for combinations of IO drugs.

Roy Baynes, Merck's head of clinical development, spoke about the potential of combos during an investor briefing at the June ASCO meeting in Chicago. "The question really goes to the issue of is there a place for monotherapy given the striking results that you are seeing reported in combinations," he said. "I think that no combination is for free; every combination comes with some baggage. It's going to be in the form of toxicity. If you could identify the patient for whom monotherapy is all that's needed, that would be a great service to that patient because there's no question that monotherapy can induce very profound, deep responses and they are very durable. [There's] no question there will be a place for monotherapy and, actually, quite a substantial place. For example, if we look at our NSCLC data, when we select patients using PD-L1 – recognizing it's not a perfect biomarker, but using that – we get a response in one out of every two patients. That's remarkable. So for about half of those patients, in fact, nothing else is probably going to be relevant."

As more companies jump aboard the IO bandwagon, no less a personage than the FDA's head of oncology products, Richard Pazdur, urged a calm on the frenzy, telling Reuters at the ASCO meeting that drug developers "should ask themselves, 'Would we be better off spending those resources into looking at more novel drugs?'"

Leerink, though, doesn't see the tide receding. "IO combination efficacy remains the key needle-mover, [with] first-line NSCLC the key battleground in late-stage development," according to its analysis. "As ownership of PD-1/PD-L1 antibodies is becoming increasingly commoditized, the race for an IO combination regimen with superior efficacy remains wide open, in our view, and holds the potential for lead player BMS to further entrench its established market position in melanoma, lung and kidney cancer, or for competitors Merck, Astrazeneca and Roche to capture significant share of an outsized market opportunity."