CHICAGO – Phase III data presented at the American Society of Clinical Oncology annual meeting on combination use of Bristol-Myers Squibb Co.’s anti-CTLA-4 Yervoy and anti-PD-1 Opdivo offers a long-anticipated answer to the question of what effect is gained by layering immune checkpoint inhibitors, but the results also raise some questions that are major themes of the meeting: what is the role of the PD-L1 biomarker, and what is the cost associated with dual immunotherapy.

The three-arm CheckMate 067 study tested the combination against Bristol’s CTLA-4 inhibitor Yervoy or its PD-1 inhibitor Opdivo (nivolumab) alone in first-line treatment of 945 patients with advanced melanoma. Bristol’s Opdivo and Merck & Co. Inc.’s competing PD-1 inhibitor Keytruda (pembrolizumab) are both approved as monotherapy for advanced melanoma, as is Yervoy.

Bristol said June 1 that FDA accepted its supplemental BLA for the combination of Opdivo and Yervoy in first-line melanoma. The filing, supported in part by the Phase II CheckMate 069 study, has priority review and a user fee date of Sept. 30 [Editor's note: this story was updated June 1 to include the submission information.]

The 067 study, presented at the plenary session on May 31, showed impressive results in the overall population, as well as stratified results that suggest different treatment approaches could be appropriate for patients with high expression of PD-L1 and patients with low levels. In the total population, median progression-free survival was 11.5 months, versus 6.9 months for Opdivo alone and 2.9 months for Yervoy, and the overall response rate was 57.6% for the combination, versus 43.7% for Opdivo and 19% for Yervoy (trial wasn’t powered for comparison for the combination vs. Opdivo, but numeric results were given). Overall survival data are not yet mature

As expected, based on earlier stage trials, using Yervoy meant a much higher rate of severe side effects Also see "Yervoy/Nivolumab May Need Stronger Survival Data To Be First Choice In Melanoma" - Pink Sheet, 2 June, 2014.. For the combination arm, the rate of Grade 3/4 events was 55%, compared to 16.3% for Opdivo alone and 27.3% for Yervoy monotherapy. The most common were diarrhea and rash. In the combination arm, the drop-out rate was 36%, yet many of those who dropped out had a response during and/or after treatment ended. There were no treatment-related deaths in the combination arm, which investigators attribute to good management and use of guidelines. Adverse events were manageable and reversible, they reported.

Yervoy, which is given in a fixed set of treatments, has a set price of about $131,000. Opdivo, which is given indefinitely, costs $12,500 a month, or about $150,000 annually.

While oncology pricing continues to rise, industry execs have acknowledged that combinations of expensive innovative treatments will need new models, such as discounts on individual prices when drugs are used together.

“Obviously, we would like to separate who needs the combo, and who can get away with [a] PD-1 [inhibitor] by itself,” ASCO spokesperson and melanoma expert Steven O’Day commented in an interview at the conference.

Should The Population Be Selected?

Appropriate patient selection is still an important issue for the PD-1/L1 drugs, and the CheckMate 067 results were stratified by expression of the PD-L1 biomarker, a controversial measure but still the most established marker for the class of PD-1 and PD-L1 inhibitors to date.

Researchers presented data for the overall population, and also for those with different levels of PD-L1 expression (at least 5% and less than 5%). About 75% of the patient population in the study were in the <5% group,="" which="" suggests="" that="" the="" cutoff="" is="" much="" higher="" than="" what="" other="" sponsors="" are="">

One of the most intriguing aspects of the study was the analysis of results, stratified by expression of the PD-L1 biomarker. In those with higher expression of PD-L1, the response rate was 57.5% in the Opdivo arm and 21.3% for Yervoy monotherapy, compared to 72.1% for the combination. In the PD-L1 low patients, the response rate was 41.3% for Opdivo alone and 17.8% for Yervoy monotherapy, compared to 54.8% for the combination.

Median PFS for the high PD-L1 patients was 14 months for the combination, which was exactly the same as for Opdivo alone, and much higher than for Yervoy alone (3.9 months). However, in patients with low levels of PD-L1, there was a big numerical difference in PFS for the combination compared to Opdivo alone –11.2 months vs. 5.3 months. (Median PFS for Yervoy alone in the <5% arm="" was="" 2.8="">

Toxicity did not correlate with PD-L1 status.

The PFS figures suggest that the combination is worthwhile in patients with lower levels of PD-L1 expression, but in patients with higher levels the combination is not better than PD-1 monotherapy.

Bristol said that through the sub-analyses, the CheckMate 067 trial allows for better understanding of the efficacy of the combination based on PD-L1 expression in patient tumors. The Opdivo/Yervoy regimen demonstrated numerically longer PFS and a higher objective response rate than Opdivo monotherapy in the overall population, the company noted, but “based on tumor PD-L1 expression, the greatest benefit of the regimen in PFS and ORR was seen in PD-L1 low- and non-expressing tumors.”

Discussing results during the plenary, Michael Atkins, Georgetown University Lombardi Comprehensive Cancer Center, however, noted limitations of the PD-L1 biomarker and advised against its use for management at this time. Echoing sentiments expressed multiple times for PD-1/L1 trials throughout the weekend, he deemed the PD-L1 biomarker “not good enough to use for patient decision-making.”

Potential For Precision Medicine

The CheckMate 067 results raise questions about PD-1 monotherapy in patients with higher expression of the biomarker. During the press briefing, lead investigator Jedd Wolchok, Memorial-Sloan Kettering, said that the results suggest that patients who have higher PD-L1 expression are likely to get the same PFS benefit with Opdivo monotherapy as if they took the more toxic combination (median PFS was 14 months for both).

“It’s a way to try and introduce a precision aspect to immunotherapy. It’s this study, we see that it is a way to initiate meaningful conversations between patients and clinicians about whether the combination is the right fit for them, versus nivolumab alone,” Wolchok said.

In melanoma, PD-L1 expression is very common and should not be used to determine who treatment with a PD-1 inhibitor, however, it could be useful in guiding who gets more aggressive treatment. O’Day told “The Pink Sheet” DAILY.

It does seem to be emerging as a more useful measure in lung cancer – Bristol, Merck and Roche all presented studies over the weekend supporting the role of PD-L1 expression in selecting patients in that setting ([A#14150601001]).

Commenting on the plenary discussion, O’Day said that he agrees with Atkins that “PD-L1 is not a perfect marker and some would say not ready for prime time,” but it is a good start and very low PD-L1 expression suggests strongly that the combo is best.

Cutoff levels and individual assays for PD-L1 differ between companies and labs, so much work needs to be done, he added.

What This Means For Yervoy

The CheckMate 067 results are remarkable and clearly show that the combination and Opdivo alone are better than Yervoy alone, O’Day, director of immuno-oncology at the John Wayne Cancer Institute, commented during the interview.

Yervoy is “still an important part of the equation,” based on its different and complementary mechanism of action, in O’Day’s view. PD-L1 expression is a sign that of an immune system response, and PD-L1 inhibitors work when that immune response is activated, he explained. Yervoy has a different mechanism that works in an earlier stage, activating the T-cells to enable a response.

Yervoy monotherapy relatively recently became the standard of care in first-line melanoma, following approval in 2011. But Yervoy is now moving to the second line of therapy, following PD-1 inhibitors, said O’Day, who was the lead investigator on the first high-profile Phase III study of ipilimumab, presented in a plenary session at the ASCO meeting in 2010 Also see "Ipilimumab Boosts Survival, But With Adverse Events That Need Strict Oversight" - Pink Sheet, 6 June, 2010..

However, O’Day also noted that his comments were based on the expectation that PFS would translate to an overall survival benefit, which has historically been the case with immunotherapies.

Now the question is whether the Yervoy/Opdivo becomes the new standard of care for first-line melanoma, or whether the better tolerated PD-1 monotherapy will take and keep the frontline position.

Opdivo/Yervoy Data Show Role For Checkpoint Combos; ASCO Debates Biomarkers

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