If you thought you knew what was coming in Bristol-Myers Squibb’s CheckMate-227 trial, forget it.

The company’s star immunotherapy Opdivo won one segment of that lung cancer test and lost another as some expected. But in a big surprise, it wasn’t the Opdivo-chemo combo that hit its marks.

Instead, Opdivo and its frequent tandem partner Yervoy showed they could help previously untreated patients with non-small cell lung cancer live longer, provided their cancers tested positive for the PD-L1 biomarker. Those results spanned the squamous and far more common non-squamous forms of the disease.

The trial results "are a win and a miss, but in an unexpected direction," Wolfe Research analyst Tim Anderson wrote Wednesday evening. And Anderson figures that might end up playing in Bristol-Myers’ favor; the Opdivo-Yervoy pair offers chemo-free treatment, something certain patients and doctors might go for, given chemo’s bad rep for side effects.

Why were market-watchers expecting that duo to miss? The pairing of a PD-1 drug—in this case, Opdivo—and a CTLA-4 partner had been tarnished in previous lung cancer trials, including a high-profile test of AstraZeneca’s Imfinzi plus tremelimumab.

Meanwhile, the chemo combo that won big for Merck & Co.—whose PD-1 med Keytruda paired with chemo barreled into first-line lung cancer in May 2017—didn’t deliver for BMS.

Opdivo plus chemo failed to beat chemo alone at helping previously untreated patients with non-squamous NSCLC live longer, regardless of PD-L1 status, Bristol-Myers said Wednesday. The IO combo did deliver a numerical advantage, both in overall survival and one-year survival rates, but not enough to call it a win.

Patients treated with Opdivo plus chemo lived a median 18.83 months compared with 15.57 months among those treated with chemo alone. And at the one year mark, 67.3% of the Opdivo-chemo patients were still alive, compared with 59.2% of the patients on chemo alone.

The shortfall was "not the outcome we had hoped for," oncology chief Fouad Namouni, M.D., said in Wednesday's statement. 

By contrast, in the Opdivo-Yervoy segment of the study, the BMS combo hit its goal on overall survival, extending a progression-free survival beat last year. Opdivo-plus-Yervoy beat chemo alone at extending patients’ lives, provided their PD-L1 levels hit 1% or more. The patient pool included those with non-squamous and squamous types of lung cancer.

Plus, an "exploratory" analysis showed Opdivo-Yervoy benefits might just apply to PD-L1-negative patients, too.

If BMS can parlay the trial results into a new first-line approval, that could offer a sales boost, executives said during the company's Q2 conference call. Opdivo grew by 12% to $1.83 billion worldwide, while Yervoy turned in a 17% increase to $367 million.

Analysts sliced and diced the trial numbers, and pointed out that chemo’s performance in CheckMate-227 matched up to historical figures, whereas in Keytruda’s first-line trial, chemo patients performed less well than might have been expected—a fact noted at the time.

That could account for the larger spread for Keytruda, they posited, though Evercore ISI’s Umer Raffat also pointed out that the Keytruda-chemo combo extended patients’ lives for more than 20 months at the median, compared with Opdivo-plus-chemo’s 18.83 months.

It’s always hazardous to directly compare trial results, but investors commonly do so, and so do doctors when choosing which meds to use in their patients—fair or not.

In any case, it’s obvious that Keytruda is the checkpoint inhibitor to beat in lung cancer at this point, given its head start in the first-line setting, which is the biggest pool of patients. Bristol-Myers has been handicapped there for more than two years now, and its own second-line prospects diminished by the expected leaching-away of patients as Keytruda penetrates the previously untreated group.

But as Anderson also pointed out Wednesday, the Opdivo-Yervoy pairing hinted it did work regardless of PD-L1 status—and there’s a bigger unmet need in patients whose tumors test negative for the PD-L1 marker.

Bristol-Myers will presumably unveil full data from the CheckMate-227 trial at the European Society for Medical Oncology Congress this fall. Until then, a comprehensive assessment of the results is impossible.

"Without knowing detailed results—most importantly, the magnitude of the clinical benefit—it is hard to say much more, but hitting on OS would strongly imply an approvable regimen," Anderson noted, going on to say, "It will be equally important to see the safety/tolerability of Opdivo+Yervoy ... the net is that Opdivo+Yervoy may finally be able to position itself as a chemo-free option in first-line non-squamous lung cancer."

Even though it missed on the chemo-combo side, prospects for the Opdivo-plus-Yervoy combo and its chemo-sparing advantage could help offset that. "[S]ome patients will invariably seek to avoid chemotherapy and preference IO/IO," Anderson figures.

We’ll have to wait a couple of months to see exactly what BMS might yield here. The company pulled its previous first-line app for lack of data. And the chemo-combo setback is significant. Keytruda has a big lead in the first-line market, too—and recently put up impressive five-year survival results. But for the first time in a long time, Bristol has higher hopes for a piece of it.