After the surprise failure of Bristol-Myers Squibb’s (NYSE:BMY) Checkmate-026 trial of Opdivo in non-small cell lung cancer last week, the degree of PD-L1 expression looks like remaining an important factor in this indication for the foreseeable future. This was until now a questionable point.
The first-line flop also brings into play several other trials that had until now seemed relatively unimportant (see table below). AstraZeneca’s (NYSE:AZN) durvalumab, Pfizer (NYSE:PFE) and Merck KGaA's (OTCPK:MKGAF) (OTCPK:MKGAY) avelumab and Roche’s (OTCQX:RHHBY) Tecentriq have suddenly gained a new opportunity in the first-line setting, which until recently Opdivo looked like it was going to dominate.
Pfizer and Merck KGaA are running the JAVELIN Lung 100 of avelumab in first-line NSCLC. The primary endpoint concerns patients with PD-L1-positive tumors, with a threshold set at 1% like Checkmate-026, though a secondary endpoint includes PFS in strongly PD-L1-positive tumors; data are expected in August 2017.
However, another consequence of the Checkmate-026 failure will be growing interest in dual therapy first line, as this is less reliant on high levels of PD-L1 expression. Astra’s Mystic trial reads out in early 2017, before JAVELIN Lung 100, testing durvalumab monotherapy as well as a combo with Astra’s anti-CTLA4 antibody tremelimumab.
A separate combination approach, most prominently being tested by Roche, is to combine immuno-oncology with chemotherapy, which is thought to increase the immunogenicity of the tumor micro-environment.
The first trial of this approach is IMpower150, pitting Tecentriq in combination with carboplatin/paclitaxel and Avastin against chemo alone. However, it is limited to non-squamous patients, as Avastin is not indicated in those with squamous histology.
A single-agent Tecentriq study, IMpower110, tests the drug against a platinum doublet chemotherapy in PD-L1-positive, non-squamous patients. Merck & Co., (NYSE:MRK) meanwhile, has a Keytruda chemo-combination study, Keynote-189, scheduled to read out in September 2017 – much earlier than the Roche trials.
Of course, Opdivo is still in the game, and Bristol’s focus now shifts to its combination with Yervoy; a single-arm phase II study, Checkmate-568, is to render results early next year.
However, the opportunity will be accessed on the basis of the large Checkmate-227 trial testing separate cohorts of PD-L1-positive and negative patients. The former receive Opdivo with or without Yervoy against platinum doublet therapy, while the latter get either the two-drug combination or Opdivo and chemo. Results are not due until January 2018, though there could be an earlier interim analysis.
Still, based on Checkmate-026, the Opdivo monotherapy arm in Checkmate-227 looks unlikely to succeed (Bristol swings for the fences and strikes out, August 5, 2016).
The failure of Checkmate-026 has given an immediate advantage to Merck & Co.’s Keytruda, which is likely to be the only anti-PD-1 agent used first line. Though it has yet to be approved, it will likely be limited to the 30% of patients who are high PD-L1 expressers (>50%), the population tested in Keynote-024.
Citi’s (NYSE:C) Andrew Baum argues that Keytruda’s lead could be short-lived, given upcoming data from Mystic and Checkmate-227. In the meantime, Bristol, which in Checkmate-026 had looked at a broad patient population (>5% PD-L1 expression), is expected to conduct exploratory analyses at 10%, 20%, and 50% expression – a best-case scenario would show equivalence to Keytruda, allowing Opdivo to gain a compendia listing for first-line NSCLC.
Both agents are approved for second-line NSCLC – Keytruda limited to those who test positive for PD-L1, while Opdivo has no such requirement. In practice, this gave Bristol a huge advantage, as doctors preferred to initiate therapy as soon as possible without waiting for a PD-L1 test result to come back from the lab.
A knock-on effect of Checkmate-026 is likely to be that most, if not all, patients will be tested for PD-L1 status in NSCLC, and as some become eligible for Keytruda first line, the pool of immunotherapy-naive second-line patients will diminish.
Second-line competition will also increase if other agents are approved, notably Roche’s Tecentriq. Pivotal data from Roche’s Oak study in second-line NSCLC are expected this year. Meanwhile, full data from Keynote-024, statistically significant for PFS and OS, are likely to be one of the most keenly awaited presentations of the Esmo conference in October.
And there will be much interest in the detailed results of Checkmate-026, as these could give competitors a chance to adapt their statistical analysis plans to give their own studies a better chance of success.
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