Bristol Myers details Opdivos presurgery lung cancer win, with an early sign of survival benefit

April 12, 2022:

The FDA nod for Bristol Myers Squibb’s Opdivo for treating early-stage non-small cell lung cancer (NSCLC) before surgery came so quickly in March, the company had yet to publicize results from an important marker measuring disease worsening. Now, we have details on what triggered the quick FDA action.

In a new revelation, Opdivo’s addition to chemo cut the risk of death by 43% when given before surgery to patients with resectable NSCLC, according to data presented at the American Association for Cancer Research annual meeting. At two years, 83% of patients on the Opdivo combo were alive, versus 71% for the chemo-alone group.

Although the 43% showing, gleaned from an interim analysis of the phase 3 CheckMate-816 trial, has yet to cross the statistical significance bar, it marked a “very positive trend,” Mark Rutstein, M.D., vice president of Opdivo development at BMS, said in an interview with Fierce Pharma.

Before they fully mature, the key life-extension data now may serve as supporting evidence for Opdivo’s strength in this neoadjuvant NSCLC setting. As previously announced alongside the go-ahead, the Opdivo regimen significantly reduced the risk of disease recurrence, progression or death by 37%, with a minimum follow-up of 21 months. On that event-free survival marker, Opdivo showed a benefit across patient subgroups, Rutstein noted.

The Opdivo go-ahead in presurgical, neoadjuvant NSCLC covers a broad range of patients, regardless of the tumor PD-L1 status, as long as they have resectable tumors. In contrast, an earlier green light the FDA granted to Roche’s Tecentriq for the postsurgery, adjuvant setting only allows the PD-L1 inhibitor in stages 2 to 3a disease with PD-L1 expression of at least 1%.

Rutstein acknowledged that Opdivo’s effect did appear better in patients with higher PD-L1 expression and in more advanced stage of disease, but he stressed that all other patients also benefited and that, given the trial's statistical design, the full randomized population data set is the “most impactful.”

Specifically, in exploratory analyses, Opdivo and chemo reduced the event-free survival risk by 76% in patients with PD-L1 above 50%, by 42% among those with PD-L1 expression between 1% and 49%, and by 15% in PD-L1 nonexpressors.

In patients with stage 3a disease, the Opdivo regimen pared down the event-free survival risk by 46%, while the reduction was just 13% in the subgroup of stages 1b to 2.

Speaking about the 37% benefit in all randomized patients, SVB Leerink analyst Daina Graybosch, Ph.D., said she believes Opdivo could have a “pretty strong uptake” in neoadjuvant NSCLC “given the biologic rationale.”

When it comes to the debate of whether immuno-oncology agents like Opdivo and Tecentriq should be used before or after surgery, Graybosch said she thinks before surgery is the right place “where you still have tumor to stimulate the immune system.”

In CheckMate-816, the Opdivo-chemo combo and solo chemo showed similar rates of grade 3 and 4 treatment-related side effects, and 83% of patients went on to receive surgery for the Opdivo-plus-chemo group, versus 75% with chemotherapy.

“I could almost see less debate about neoadjuvant than adjuvant because [neoadjuvant] gives you this benefit, it’s clear, it’s a short duration, lower risk of side effects,” Graybosch said in an interview with Fierce Pharma.

As PD-1/L1 inhibitors are now available for both presurgery and postsurgery treatment, the question remains as to whether patients should get the drug continuously in both settings, especially those who already have no sign of cancer in their resected tissues after neoadjuvant therapy.

In an exploratory analysis, those who had no sign of cancer in resected tissues had an 87% lower risk of disease worsening or death than those who didn't. The data highlight the importance of achieving that pathological complete response to see a clinical benefit.

Rutstein hopes the scientific community will begin to answer that question to some extent with data from more clinical trials. Besides the current CheckMate-816 study, BMS is also running the CheckMate-77T trial, which tests Opdivo as both neoadjuvant and adjuvant treatment in stages 2a to 3b NSCLC. A National Cancer Institute-sponsored trial, dubbed ANVIL, is evaluating Opdivo after surgery and chemotherapy in stages 1b to 3a NSCLC. FiercePharma