It was just March when Merck & Co.’s Keytruda landed an FDA go-ahead to treat newly diagnosed esophageal cancer. Now, Bristol Myers Squibb hopes two of its Opdivo regimens can stand toe to toe with its archrival, although one comes with a caveat.
Opdivo, used in tandem with either chemotherapy or BMS’ CTLA-4 inhibitor Yervoy, significantly extended the lives of patients with advanced esophageal squamous cell carcinoma (ESCC) compared with chemotherapy alone, according to data unveiled at the American Society of Clinical Oncology annual meeting.
Compared with chemo, the Opdivo-chemo combo slashed the risk of death by 26%, while the dual immuno-oncology pairing of Opdivo and Yervoy pared down the risk by 22%. Both numbers from the phase 3 CheckMate-648 trial are statistically significant and, as the study’s lead investigator Ian Chau, M.D., pointed out in a statement, are also clinically meaningful.
Patients on Opdivo and chemo lived a median 15.4 months, and those who got Opdivo plus Yervoy lived 13.7 months versus 9.1 months for the solo chemo group.
As expected with a PD-1 therapy, the improvements were more pronounced in patients whose tumors tested positive for the PD-L1 biomarker. In patients with PD-L1 expression of at least 1%, the death risk reduction rose to 46% for the Opdivo-chemo combo and to 36% for the Opdivo-Yervoy cocktail.
Doctors will face a choice between Opdivo’s two pairing partners—chemo or Yervoy—if both regimens are approved.
The magnitude of survival benefit was bigger for the Opdivo-chemo regimen, even though the trial wasn’t set up to compare that duo to the Opdivo-Yervoy pairing.
But as Chau noted during a press briefing ahead of the official presentation, patients with squamous cell disease often have certain health conditions, such as impaired kidney function, that preclude chemo use.Chau said he would opt for the chemo regimen in patients with a high symptomatic burden or high tumor burden as long as the patient is fit enough to tolerate chemo.
That’s because in addition to the life-extending benefits, more patients responded to the Opdivo-chemo cocktail than to the dual I-O therapy. Opdivo and chemo significantly shrank tumors in 47% of patients, versus 28% for Opdivo and Yervoy.Plus, the I-O doublet also failed to beat chemo at stalling tumor progression.
In defending that use during an interview, Jonathan Cheng, BMS’ head of clinical oncology, pointed out that overall survival is the gold standard in measuring efficacy in cancer research and life extension is what patients care about most.
BMS sure hopes that more doctors will use two of its drugs rather than just one, but the Yervoy regimen has one caveat.
All the previous data were calculated at a median follow-up of 13 months. But during the first six months post-treatment, more patients—both for the PD-L1-positive group and the all randomized population—died while on Opdivo and Yervoy compared with the chemo group. The overall survival curve only started to move in favor of the BMS drugs afterward.
Chau said the investigators are still trying to understand the characteristics of this group of patients who tend to die earlier with dual I-O and warned that they may not be able to identify this patient subgroup. He also noted that this patient survival pattern is “quite frequently observed especially in [gastrointestinal] cancers.”
Keytruda itself showed similarly worse survival performance during the first few months of treatment in PD-L1-positive stomach cancer when compared with chemotherapy in the failed Keynote-061 and Keynote-062 trials.
The CheckMate-648 trial now lines up Opdivo for a potential FDA green light to challenge Keytruda in ESCC. Opdivo-plus-chemo already won approval for previously untreated esophageal adenocarcinoma in a landmark approval that also covers stomach cancer. About a third of newly diagnosed esophageal cancers belong to the squamous cell subtype.
Keytruda recently earned its go-ahead for all previously untreated esophageal cancer thanks to data from the phase 3 Keynote-590 trial. Among ESCC patients enrolled in that trial, Keytruda and chemotherapy reduced the risk of death by 27% over chemo. In ESCC patients whose tumors expressed PD-L1 at a combined positive score of at least 10, the risk decrease widened to 43%.
Besides advanced esophageal cancer, BMS a few days ago snagged an FDA approval for Opdivo as a post-surgery treatment for completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease after presurgery chemoradiotherapy. It came off data showing Opdivo could reduce the risk of disease recurrence or death by 31% over placebo.