In the race for leadership in the treatment of early-stage non-small cell lung cancer (NSCLC), Bristol Myers Squibb has put up trial data that look competitive to those from Merck’s Keytruda. But a key debate remains unsettled.
Adding Opdivo before and after surgery on top of presurgical chemotherapy alone reduced the risk of tumor recurrence, progression or death by 42% in patients with stage 2 to 3b NSCLC. The phase 3 data from the CheckMate-77T trial were shared at the European Society for Medical Oncology 2023 congress.
Opdivo’s 42% improvement on the event-free survival (EFS) marker was identical to Keytruda's showing in its own Keynote-671 trial in the same treatment setting. Opdivo achieved its result after a median follow-up of 15.7 months, while the Keytruda data came from a median follow-up of 25.2 months.
“We will certainly have a competition with Keytruda,” BMS’ chief medical officer, Samit Hirawat, said in an interview ahead of Opdivo’s data release. “And certainly, we see ourselves as an effective treatment and certainly something that is going to be good for the patients.”
Keytruda this week won FDA approval as part of a continuous neoadjuvant-plus-adjuvant regimen for resectable NSCLC. Besides the EFS win, the Merck drug also slashed the risk of death by 28% in Keynote-671, making it the only PD-1 inhibitor to have shown a statistically significant overall survival benefit in early-stage NSCLC.
The overall survival outcome from Opdivo’s CheckMate-77T remains immature and wasn’t formally tested at this interim analysis, according to a BMS spokesperson.
For its part, perioperative Keytruda showed consistent benefit across patient subgroups, Marjorie Green, Merck’s head of late-stage oncology development said in a separate interview with Fierce Pharma.
“Ultimately, these patients are at high risk for recurrence and death. So being able to demonstrate that you can improve survival with this comprehensive regimen, we think is clinically important to patients and practitioners,” Green said.
But perioperative Keytruda and Opdivo aren’t just competing against each other.
Last year, Opdivo, used alongside chemo, earned an FDA go-ahead as a neoadjuvant therapy—without the post-surgery adjuvant component—in resectable NSCLC based on findings from the CheckMate-816 trial. And according to BMS’ Hirawat, doctors have already gotten used to using Opdivo in the neoadjuvant setting.
Doctors have been debating whether an immunotherapy is needed for both neoadjuvant and adjuvant treatment. Continued perioperative therapy means longer treatment durations and hence better sales for the drugs.
CheckMate-816 was conducted in patients with stage 1b to 3a NSCLC. That study linked neoadjuvant Opdivo to a 37% reduction in the risk of recurrence, progression or death with a minimum follow-up of 21 months. The size shrank to 32% in a long-term, three-year analysis.
The 37% EFS benefit for neoadjuvant Opdivo wasn’t all that different from the 42% figure for perioperative Opdivo or Keytruda in their respective trials. What’s more, the earlier CheckMate-816 trial used Opdivo and chemo for three cycles before surgery, while patients in the CheckMate-77T trial got up to four cycles during the neoadjuvant phase.
These cross-trial comparisons are intrinsically flawed because the studies enrolled different patient populations, but doctors and investors can only rely on them in the absence of a head-to-head trial.
An extra cycle of treatment in the neoadjuvant phase, plus up to a year of adjuvant treatment, may be a tough sell in exchange for 5-percentage-point improvement in EFS. That’s why industry watchers were counting on overall survival data to help adjudicate the debate.
Perioperative Keytruda has now shown a statistically significant 28% improvement in overall survival, while neoadjuvant Opdivo has demonstrated a 38% reduction—which didn’t reach statistical significance—in the risk of death in a longer-term follow-up of CheckMate-816.
At three years, 71.3% of Keytruda takers were alive, versus 64% in the control arm of Keynote-671. The control group in CheckMate-816 showed the same 64% three-year survival rate, while the figure was 78% for neoadjuvant Opdivo.
Merck's Green wouldn’t hypothesize whether the magnitude of Keytruda’s OS benefit will widen later in Keynote-671. Investigators will continue to follow patients, but because the trial has hit its overall survival endpoint, the 28% number is considered the final OS analysis from the trial, the exec said.
As Leerink Partners analyst Daina Graybosch, Ph.D., noted in a comment to Fierce Pharma following Keytruda’s perioperative nod, she’s interested in knowing how much doctors care about statistical significance, an advantage that Keytruda now has.