On Wednesday (May 10), the FDA approved Merck & Co.'s PD-1 inhibitor Keytruda as a combination therapy with pemetrexed and carboplatin as first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer (NSCLC), irrespective of PD-L1 status.
Newly diagnosed NSCLC represents the largest commercial opportunity for PD-1/PD-L1 inhibitors (at approximately 100,000 patients per year) and could be worth around $15 billion in peak annual sales, predict analysts. Keytruda is the only drug in class currently approved in this line of therapy.
Wasn't Keytruda already approved for some first-line NSCLC patients?
Keytruda was approved as a monotherapy to treat first-line NSCLC patients whose tumours express PD-L1 levels of 50 percent or more in October. In the Keynote-024 trial, Keytruda reduced the risk of progression or death by 50 percent compared to chemotherapy and demonstrated a 40 percent reduction in the risk of death versus chemotherapy.
Patients with PD-L1 expression levels of 50 percent or more account for between 25 percent to 30 percent of the addressable first-line NSCLC population. In its Q1 earnings call, Merck reported strong early utilisation of Keytruda in this setting; management noted that one in four of all first-line patients are now being treated with Keytruda monotherapy and the vast majority of treatment-naïve patients who meet eligibility with Keytruda's labelling receive the drug. Between 75 percent and 80 percent of newly-diagnosed NSCLC patients in the US are now being tested for PD-L1 status, as are around two-thirds of patients in the EU, the company noted.
Sales of Keytruda stood at $584 million in Q1, with approximately 40 percent accounted for by lung cancer use; sales grew by 134 percent year-on-year and sequentially by 21 percent versus revenues in Q4 2016.
How does the latest approval expand Keytruda's labelling?
FDA accelerated approval of Keytruda in combination with pemetrexed (Eli Lilly's Alimta) and carboplatin is based on tumor response rate – 55 percent for Keytruda/pemetrexed and carboplatin versus 29 percent for pemetrexed and carboplatin alone – and progression-free survival (PFS) – 13.0 months versus 8.9 months.
Approval in combination with pemetrexed and carboplatin is also agnostic to PD-L1 status, meaning that utilisation is permitted by label in null, low and high-PD-L1 expression patients. Various analysts have suggested that as a result, Merck could gain access to up to 90 percent of the first-line NSCLC market, although company management has spoken more cautiously, suggesting that Alimta-based chemotherapy regimens are only used in approximately 25 percent of US patients. These patients are where the vast majority of early utilisation is likely to occur, they noted on Merck's recent Q1 earnings call.
FirstWord's latest Physician Views snap poll should provide insight on how utilisation of Keytruda in this setting will evolve.
Does approval endorse the 'chemo-combo' approach?
Although it is recognised that chemotherapy can turn tumours immunogenic, making them more amenable to checkpoint blockade, there has been considerable debate around the merits of treating first-line NSCLC patients concurrently with a PD-(L)1 inhibitor and chemotherapy, or whether sequential treatment is more effective.
FDA approval does therefore provide the first "true endorsement" of this approach, notes Bernstein's Tim Anderson – particularly as Merck is yet to present data demonstrating an overall survival benefit for the combination – though he adds it will only quell "some of the scepticism by physician experts."
On a related note, while Merck and Roche have prioritised chemotherapy pairings for their respective PD-(L)1 inhibitors and Bristol-Myers Squibb and AstraZeneca have prioritised PD-(L)1 plus CTLA-4 inhibitor combinations, the latter two companies have subsequently moved chemo-pairings into pivotal-stage studies also; neither Merck or Roche has publicly disclosed a pivotal-stage PD-(L)1 plus CTLA-4 inhibitor combination. The tide appears to have turned more favourably towards use of chemotherapy in the near term.
What upcoming readouts could impact use of Keytruda in first-line NSCLC patients?
Readout from a succession of forthcoming combination studies hold the potential to impact future utilisation of the Keytruda/chemotherapy combination.
AstraZeneca's MYSTIC trial – initial data to readout in mid-2017 – is studying the PD-L1 inhibitor Imfinzi with the CTLA4 inhibitor tremelimumab and Imfinzi monotherapy in both all-comer and patient cohorts defined by pre-specified (but unknown) PD-L1 expression cut-offs. A change in study design could give AstraZeneca a better shot at delivering fileable data for Imfinzi monotherapy in higher-expressing patients, with a number of analysts now predicting mixed data (less statistical power to the PFS endpoint may require AstraZeneca to wait for overall survival data, which reads out later).
Merck is expected to announce results from its Phase III Keynote-189 trial in the third quarter, which could reinforce the Keynote-021 (Cohort G) data used to support last week's approval.
Roche is also expected to readout data from the Phase III IMpower 150 trail in the second half of 2017, which is assessing Tecentriq plus Avastin plus chemotherapy (and utilises a different chemotherapy regimen).
Bristol-Myers Squibb will announce results from the much anticipated CheckMate-227 trial in late 2017 or early 2018, which is assessing the combination of Opdivo with Yervoy (its CTLA-4 inhibitor). This trial could have an interim readout at any time, note analysts at Jefferies, who suggest Merck's monopoly position could be threatened if any competitor delivers overall survival data in first-line patients.
Has Merck mastered the art of navigating a difficult IO market?
This latest approval further advances Merck's lead in the NSCLC market, when a year-ago the company was locked in a head-to-head race with Bristol-Myers Squibb. Keytruda's initial approval in first-line patients – albeit in a subset of high expressers – paired with the failure of Opdivo monotherapy to demonstrate survival benefit in a broader cohort of patients, set this trend in motion. Merck then presented promising Phase II data for Keytruda plus chemotherapy at last year's ESMO meeting, but caught competitors (and investors) unaware when it announced in January it would use these to file for US approval. The combination has also been filed for approval in Europe, promoting speculation that Merck could present elusive overall survival data (with crossover largely blamed for its absence at ESMO) at next months' ASCO annual meeting.
Merck's seemingly Midas touch when it comes to all things IO was enhanced by this approval coinciding with Roche's confirmation that Tecentriq had failed to demonstrate a survival benefit in second-line bladder cancer patients (where Keytruda has; and is awaiting approval). This is the second occasion – the first being versus Opdivo in first-line NSCLC – where Keytruda has succeeded where competitors have failed.
"Keytruda's relative momentum keeps getting better," note analysts at Morgan Stanley, who add that "although the general view is that all PD-(L)1 agents are more or less the same, Keytruda's news-flow has been standing out relative to competitors." Regarding Tecentriq, they note that it was originally designed as a more narrowly targeted drug (PD-L1) to minimize toxicity when used in combination with other agents. By contrast, Keytruda is a PD-1 agent that targets both PD-L1 and PD-L2, which in clinical testing has turned out to have a relatively clean safety profile.
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