Carly Helfand, FiercePharma
AstraZeneca has had high hopes for an immuno-oncology combination of Imfinzi and candidate tremelimumab. But after a high-profile miss last year, the combo has struck out again.
Wednesday, the British drugmaker revealed that the duo had failed to extend the lives of a group of previously untreated patients with stage 4 metastatic non-small cell lung cancer when pitted against a standard-of-care chemo regimen.
But it wasn’t just any group of stage 4 patients where the combo failed. Researchers did the primary analysis among patients with high levels of mutations in their tumors, an experimental biomarker called tumor mutational burden (TMB). Companies including AZ and Bristol-Myers Squibb have said the marker could help identify patients who respond best to their therapies, but so far, trials haven’t shown that to be the case—including this one.
Full results from the phase 3 trial, dubbed Neptune, are still under wraps for now, and they’ll stay that way until AZ presents them at an upcoming medical meeting. “We are fully committed to a deep analysis of the vast clinical and biomarker data from this trial to gain further insights” the company can apply to lung cancer treatment, José Baselga, EVP of oncology R&D, said in a statement.
Imfinzi and tremelimumab have shared a troubled past. Last year, after 16 months of stoking investor hopes that the pair could help first-line lung cancer patients live longer—despite an initial trial miss—AstraZeneca unveiled results from its Mystic trial showing the combo didn’t top chemotherapy by that measure. The flop was a major blow, dashing hopes Imfinzi could enter what’s considered to be immuno-oncology’s most lucrative market.
At the time, execs pointed to an association between better survival outcomes and high TMB levels as a silver lining, hinting that it could use the biomarker to try to carve out a niche for Imfinzi in the future.
That approach hasn’t gone so well for Bristol-Myers Squibb, though. After initially filing a front-line application for its Opdivo-Yervoy combo—also composed of a PD-1/PD-L1 drug and a CTLA4 drug—in TMB-high patients, it withdrew on grounds that it needed more data to show the pairing produced better results in those patients than it did in the rest of the population.
Meanwhile, Imfinzi and tremelimumab’s struggles haven’t been limited to the lung cancer arena. Late last year, neither Imfinzi nor Imfinzi-plus-tremelimumab topped chemo in head and neck cancer, a disease where Imfinzi’s rivals are already approved.
While industry watchers may once have thought that some of the combo’s problems—at least in lung cancer—could stem from the CTLA4 add-on, a recent BMS trial win threw cold water on that idea.
Previously, only IO-chemo combos—from Merck and Roche—had shown they could succeed in previously untreated NSCLC patients; Bristol and AZ both came up short with their CTLA4 pairings. Last month, though, Opdivo and Yervoy showed they could help those patients live longer, provided their cancers bore the biomarker PD-L1.
That’s not to say Imfinzi isn’t crushing it as a solo therapy in lung cancer, though. In Q2, Imfinzi—destined for blockbuster-land—put up $338 million on the back of its indication in previously treated, stage 3 lung cancer patients whose tumors can’t be removed.
And earlier in the summer, an Imfinzi-chemo combo put up a win against solo chemo in extensive-stage small cell lung cancer, a market where AZ hopes to give Roche a run for its money.
AstraZeneca is hoping it can push that luck in stage 4, too. It’s testing Imfinzi solo and in tandem with chemo—with and without tremelimumab—as part of its stage 4 NSCLC program, the company said.