New data from early studies of checkpoint inhibitors in non-small cell lung cancer emerged at Asco, but none represented the results that the oncology field is awaiting most eagerly.
This accolade is reserved for the outcome of the phase III studies of Merck & Co’s (NYSE:MRK) Keytruda and Bristol-Myers Squibb’s (NYSE:BMY) Opdivo in first-line NSCLC therapy that will likely determine how the most commercially important cancer indication divides up among competing agents. Other immunotherapies are waiting in the wings, but the initial battle hinges on the breadth of the possible NSCLC label that Opdivo and Keytruda might boast (see table below).
The Bristol and Merck drugs are both approved as second-line therapies in NSCLC, but Keytruda is indicated only for those patients whose tumour cells express PD-L1. Opdivo has no such restriction, and – with no need to conduct a companion test – has so far captured the lion’s share of NSCLC patients. In other respects the two agents are considered interchangeable, despite minor differences in efficacy and dosing schedules.
Up the chain
With these agents already established as the second-line standard, the next change in the field is expected to be a move to first-line therapy. This will be determined by the outcome of the Keynote-024 study of Keytruda, which is due imminently, and the Checkmate-026 trial of Opdivo, expected in November.
The two studies are very similar and test the drugs against platinum-based chemotherapy in the subgroup of patients who are “strong” expressers of PD-L1 – about 25% of patients. With Merck having already lost its first-mover checkpoint inhibitor advantage, the group's lead in first-line NSCLC could be a chance to even the balance against Bristol.
However, any advantage might be short-lived. This is because Bristol's study has a statistical design allowing all-comers to be tested if an initial benefit in "high PD-L1 expressors" is shown. Merck's Keynote-025 is recruiting only PD-L1-high patients.
Clearly an additional advantage can come from better efficacy. Later studies test the drugs in combination with first-line chemotherapy and/or in broader groups based on PD-L1 expression.
But what of the data in first-line therapy emerging at Asco? One closely watched presentation concerned Keynote-021, a multi-cohort phase I/II study of Keytruda plus platinum-doublet chemotherapy, immunotherapy or EGFR-targeted therapy.
In one cohort 24 patients who received Alimta, carboplatin and Keytruda as a front-line treatment followed by Alimta/Keytruda for up to two years achieved an objective response rate (ORR) of 71%. Furthermore, those with the highest level of PD-L1 expression showed a 75% ORR.
Pooled data from Checkmate-012, a phase Ib study of Opdivo and Yervoy, were also presented. Here the combination achieved an ORR of 39% to 47%, depending on dose. ORR averaged 57% in PD-L1-positive patients and reached 92% in the highest (≥50%) PD-L1 expressers. In patients who tested PD-L1-negative the ORR for the combination regimen was just 15%.
This combination is being assessed in the phase III Checkmate-227 trial, which has a projected completion date of January 2018. But competition in the NSCLC market looms, and a review by EP Vantage shows 23 phase III studies under way with PD-1/PD-L1 inhibitors.
The first threat is likely to come from Roche’s (OTCQX:RHHBY) Tecentriq, which is under review for second-line use in PD-L1 expressers, with a PDUFA date of October 19. A more direct threat could come in the form of Pfizer (NYSE:PFE)/Merck KGaA’s (OTCPK:MKGAY) avelumab, which is being studied in the first-line indication in the Javelin lung 100 study.
AstraZeneca (NYSE:AZN) has a number of phase III studies under way with durvalumab, though earlier this year it made a decision that, irrespective of their outcome, it would not file this project as monotherapy, instead seeking to build an immuno-oncology franchise based on the combination with tremelimumab. Its first study of this combination in PD-L1-negative third line-patients reads out in early 2017.
Either way, any lead that Keytruda will have thanks to its earlier data readout is likely to be short lived.
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