Bristol Should Have Opdivo First-Line Lung Cancer Data In Weeks

With Opdivo sales up to $840m in the second quarter, Bristol execs once again make the case for trial strategy in the all-important first-line lung cancer indication and say they look forward to the CheckMate 026 data “in weeks not months.”

Basking in the glow of a strong second quarter overall, Bristol-Myers Squibb Co. reported sales of $840m for its PD-1 inhibitor Opdivo and touted an 80% market share in the class, but it remained on the defensive regarding its first-line lung cancer and combination strategies – and whether it is too focused on its lead cancer immunotherapies.

There's more profit on the table, and the programmed-death checkpoint inhibitor sponsors are vying for the one of the most important market segments to date. Merck & Co. Inc. recently reported positive data in the first-line setting from the KEYNOTE-024 study of its competing Keytruda (pembrolizumab), and said it was moving fast in filing the data. (Also see "Merck Poised To Be First To Market With A PD-1 For First-Line Lung Cancer" - Scrip, 16 Jun, 2016.)

During its July 28 sales and earnings call, Bristol execs once again faced a barrage of questions about the first-line study design. But the answers will be available soon: Chief Scientific Officer Francis Cuss reported that it expects to get the data from the CheckMate 026 trial “in weeks and not months.”

Sales of Opdivo (nivolumab) were up from $704m in the first quarter and $122m in the second quarter of 2015, and were mostly in line with analyst expectations. The drug has scooped up a range of indications since its first approval in metastatic melanoma in December 2014 and now has additional indications in second-line non-small cell lung cancer (squamous and non-squamous), renal cell cancer and Hodgkin lymphoma. Opdivo was also approved for use in combination with Bristol's CTLA-4 inhibitor Yervoy (ipilimumab) in first-line metastatic melanoma in the US in October 2015 and won European approval for this indication in May.

Yervoy, which is indicated for melanoma, continued to struggle in the second quarter amid competition from PD-1 inhibitors. Sales of $241m were down by 19% from $296m in the same time in 2015, lower than analyst expectations. While Yervoy sales were down by 19% overall, sales in the US, where the combo is approved, were up by 32% to $179m.

The company reported that the combination regimen has become been well accepted in the US and has broad insurance access. However, Chief Financial Officer Charles Bancroft said during the earnings call that the company also expects pressure to continue internationally until the company secures reimbursement over the next year, following approval of the combination in Europe.

In a July 28 note, Credit Suisse analyst Vamil Divan observed that Opdivo sales were exactly in line with his firm’s expectations, but that “investors may have been hoping for a somewhat stronger quarter,” especially with Yervoy coming in light.

However, for pharma products overall performance exceeded expectations. The company reported sales of $4.9bn, up 17% from the same time last year, and including $2.7bn in US sales, up 46%. Opdivo was the firm's top seller.

Opdivo In Dominant Position

CEO Giovanni Caforio noted that physician adoption of Opdivo has been strong and that the drug has about an 80% share in the US and other key international markets, notably Germany and France.

Bristol declined to break down sales and market share by indication. Asked about the extent of off-label use in NSCLC, Bristol said that in the US, penetration in first-line squamous NSCLC was in the 10%-15% range and about 5% in first-line non-squamous NSCLC.

As with previous calls, the company faced numerous, detailed questions about its strategy for Opdivo in first-line NSCLC and expectations for pivotal trial results.

Opdivo has been leading the immuno-oncology field, with about $1bn in sales for 2015 compared to $560m for Merck’s Keytruda.

The two companies have applied different development strategies, which once again drew scrutiny during the second-quarter call.

Merck enrolled patients with at least 50% expression of the PD-L1 biomarker in the first-line KEYNOTE-024 study, estimated to be 25% to 30% of the NSCLC population, on the belief that is the group most likely to respond to PD-1 inhibitors.

Bristol enrolled patients with at least 1% PD-L1 expression, equivalent to about 70% of the first-line population. However, in the CheckMate-026 trial, the efficacy endpoints are based on an undisclosed, higher PD-L1 cut-off than the 1% for the overall trial population.

The company will also be able to assess the effects in patients with at least 50% PD-L1 expression, Cuss told the call, adding that as he has said in the past, he is confident about the design of the CheckMate 026 study.

Both companies use progression-free survival as a primary endpoint and overall survival as a secondary endpoint.

Cuss reminded analysts that the company can still file for approval without a positive OS result.

The company was aware of the opportunity for OS to be confounded in the study by crossover to Opdivo therapy. But it took steps to help to minimize this risk. For example, it made sure that patients crossing over are required to have their disease progression confirmed through a central process.

PFS and OS tend to go together but that is not a foregone conclusion; having PFS alone provides the company with a “good opportunity to make a submission and move very quickly,” Cuss said.

In a July 28 note, BMO Capital Markets analyst Alex Arfaei interpreted the remarks as a positive for Bristol and a negative for Merck.

“We believe this suggests that there are a significant number of patients with at least 50% PD-L1 enrolled in CM-026 that would allow this analysis, which would also provide an apples-to-apples comparison vs. Merck’s KN-024 study,” Arfaei wrote.

Enrollment of enough of the 50%+ patients to make an analysis “significantly increases the probability that the trial will also show a positive OS benefit,” he said.

This will help the drug compete with Keytruda on OS, but the drug also has potential to get a broader label for patients with lower PD-L1 expression in the study, he said.

Chance For Early Combo Read-Out

Bristol is also testing Opdivo in combination with Yervoy in first-line NSCLC in the CheckMate 227 study. The combo performed well in the Phase Ib CheckMate 012 study in first-line NSCLC presented at the American Society of Clinical Oncology annual meeting, which also featured promising results for the regimen in other tumor types including small-cell lung cancer and MSI-high metastatic colorectal cancer. (Also see "Bristol's Oncology Strategy: Cover All The Bases To Keep The Lead" - Scrip, 4 Jul, 2016.)

Analysts questioned whether the association of Yervoy with pseudo-progression, more so than PD-1 inhibitors, could have a negative impact in terms of the co-primary PFS endpoint in the trial.

Cuss noted that the company has generated a lot of data about Yervoy as a monotherapy as well as in combination with Opdivo, and assured analysts that this issue had been appropriately taken into account in the design of the ‘227 study.

Bristol has estimated the final read out for ‘227 will be in early 2018 but, as with all studies, it has built in options, Cuss said. It’s likely that data for patients with higher PD-L1 expression will read out first and there may be an opportunity to look at the co-primary PFS endpoint earlier than OS.

Asked whether the company was focusing too much on the Opdivo/Yervoy combination, Bristol execs stressed their commitment to developing other mechanisms of action. During the ASCO 2016 meeting, the company highlighted many different immuno-oncology targets, including effector T-cell mechanisms (e.g. CD137), non-effector T-cell mechanisms (e.g. CSF1R), targeted drugs (BCR-Abl) and NK cell mechanisms (e.g. SLAMF7). (Also see "Bristol Pushes Pedal To Metal In Immuno-Oncology Combo Testing" - Scrip, 4 Jul, 2016.) The company also recently launched an adaptive design platform called FRACTION to rapidly test new combinations.

During the second-quarter call, Bancroft highlighted the acquisition in July of Cormorant Pharmaceuticals AB, which brought in an antibody program targeting interleukin-8.

Cuss said that the company sees the opportunity to develop the next wave of combinations and that it will be bringing forward the best combinations.

“So we're not just putting our eggs all in one basket, we're keeping a very open mind and trying to drive forward the great opportunities in I-O,” Cuss said.