Stage set for checkpoint inhibitor showdown in lung cancer

The rivalry between Merck & Co and Bristol-Myers Squibb (BMS) in melanoma has now been extended into lung cancer – but the winner of the contest is hard to predict.

Earlier this month, BMS scored the first US FDA approval for a PD-1 inhibitor in non-small cell lung cancer (NSCLC), getting a green light for its Opdivo (nivolumab) drug as a second-line treatment for patients with the squamous cell form of the disease.

Merck struck back shortly afterwards, claiming US approval for its Keytruda (pembrolizumab) as a second-line therapy for all NSCLC patients – i.e. squamous and non-squamous – provided their tumours test positive for expression of PD-L1, the ligand that binds to the PD-1 receptor.

Late last week, BMS seemed to have pulled ahead of its rival with an FDA approval to extend Opdivo's label to include non-squamous as well as squamous NSCLC, and no need for a biopsy to check for PD-L1 status.

As a result, the success of the two drugs in NSCLC appears to hinge on how much importance doctors and healthcare payers attribute to PD-L1 expression as a predictor of response, something that was addressed by the FDA in its press release on Opdivo's latest approval.

"There is still a lot to learn about the PD-1/PD-L1 pathway and its effects in lung cancer, as well as other tumour types," commented Richard Pazdur, who is in charge of the FDA's Office of Hematology and Oncology Products.

"It appears that higher expression of PD-L1 in a patient's tumour predicts those most likely to benefit," he added.

BMS points to high survival rates for Opdivo monotherapy, regardless of PD-L1 expression, as evidence that its broad-based approach is valid. Meanwhile, Merck has also acknowledged that the picture is far from clear.

The company's R&D chief Roger Perlmutter said earlier this year that while the likelihood of a response to Keytruda was higher in patients with 50 per cent or greater PD-L1 expression, it had seen responses in patients with low, or even zero, levels of the biomarker.

Nevertheless, with both Opdivo and Keytruda costing upwards of $100,000 a year, the big question now is whether payers will request PD-L1 testing as a prerequisite for approving therapy with PD-1 inhibitors, or be happy to accept the 'all-comers' approached taken by BMS in its development programme for Opdivo.

Analysts at Morgan Stanley, Bernstein and Goldman have previously indicated that PD-L1 status should not be an issue, suggesting a big win for BMS versus Merck, although others have suggested that it will have an impact.

The opposing camp will point to data on Roche's checkpoint inhibitor candidate atezolizumab (MPDL3280A) which specifically targets PD-L1 and reinforced the importance of PD-L1 expression measuring.

In the phase II POPLAR trial, reported at this year's American Society of Clinical Oncology (ASCO) meeting, it was shown that PD-L1-negative patients fared worse than PD-L1-positive patients on atezolizumab, with the level of expression correlating with improvement in progression-free survival (PFS).

The data also suggested that PD-L1-negative patients had a shortened PFS compared to docetaxel. If that result was also shown in other studies it could have a bearing on the expected shift in usage of PD-1 inhibitors into the first-line NSCLC setting, as traditional chemotherapy may be preferred in some patients, at least until combination data with PD-1 inhibitors and chemo or other immuno-oncology drug such as CTLA4 inhibitors is available.