After two high-profile late-stage trial flops, AstraZeneca has finally scored a victory for Imfinzi and ill-fated tremelimumab in newly diagnosed metastatic non-small cell lung cancer (NSCLC). But in a lucrative field where immuno-oncology rivals Merck and Bristol Myers Squibb have established a solid presence, a detailed look at the data reveals a win that’s perhaps too little, too late.
A cocktail of Imfinzi, investigational CTLA-4 inhibitor tremelimumab and chemotherapy pared down the risk of death by 23% over chemo alone in previously untreated patients, AZ announced Thursday at the 2021 World Conference on Lung Cancer virtual meeting.
The phase 3 POSEIDON trial came after two prior phase 3 flops for Imfinzi in metastatic NSCLC and marked the first positive pivotal readout for treme after many more failures in multiple indications. But the data don’t look favorable compared to Merck’s Keytruda or Bristol Myers’ Opdivo, and efficacy in some patient subgroups showed imbalances that could limit an eventual FDA approval if AZ gets one.
First off, the combination of Imfinzi and chemo failed to significantly outdo chemo alone at extending patients’ lives. That pairing only reduced the risk of death by 14% over chemo alone. That already makes Imfinzi look inferior to current standard-of-care Keytruda.
Keytruda’s combo with chemo is well known for its impressive 51% death risk reduction over chemo alone in front-line non-squamous NSCLC. Those were the results at an interim analysis in the phase 3 Keynote-189 trial, while the final analysis at 31 months of follow-up showed a 44% risk decrease. As for front-line squamous cell NSCLC, Keytruda and chemo reduced death risk by 36% at interim and 29% at final analysis in the KEYNOTE-407 trial.
Luckily for AZ, treme finally pulled through to help Imfinzi. The CTLA-4 agent has a bad track record with Imfinzi and has been marred with failures in NSCLC as well as small cell lung, head and neck and bladder cancers. In front-line NSCLC alone, the dual immunotherapy combo of Imfinzi and treme flopped the phase 3 MYSTIC trial in a broad patient group and the NEPTUNE trial in patients with high tumor mutation burden.
Now that the Imfinzi-treme-chemo doesn’t appear likely to shake up Keytruda’s dominance, what about less competitive Opdivo? Data don’t look very promising for AZ.
For one thing, while the chemo-free regimen of Imfinzi and treme failed, Opdivo’s own CTLA-4 combo with Yervoy is approved for front-line NSCLC patients whose tumors express PD-L1.
For a better apple-to-apple comparison, the Opdivo-Yervoy-chemo combo won an FDA nod last year for front-line NSCLC patients regardless of PD-L1 status. In the CheckMate 9LA trial, Opdivo, Yervoy and chemo were able to show a survival benefit early, having cut patients’ risk of death by 31% over chemo after a minimum follow-up of 8.1 months. After a longer follow-up of at least 24.4 months, the rate stood at 28%, as patients on the Opdivo-Yervoy-chemo regimen lived a median 15.8 months versus 11 months for the solo chemo group.
Imfinzi-treme-chemo’s 23% death reduction looks slightly weaker than Opdivo-Yervoy-chemo’s 28%, but cross-trial comparisons have their problems. In POSEIDON, patients on the AZ therapy lived a median 14 months, versus 11.7 months for those who took chemo alone.
To further complicate the front-line NSCLC landscape, Roche’s PD-L1 inhibitor Tecentriq is allowed as a monotherapy for PD-L1-high patients thanks to data from the IMpower110 trial. And its combo with Avastin and chemo has an approval for non-squamous disease after showing it reduced the risk of death by 22% over Avastin and chemo.
Sanofi and Regeneron’s Libtayo also bears a monotherapy nod in front-line PD-L1-high NSCLC. The companies recently found that adding Libtayo on top of chemo could further prolong the lives of first-line patients in the phase 3 EMPOWER-lung 3 trial.
Eli Lilly and Innovent Biologics have a front-line non-squamous NSCLC filing for their China-approved PD-1 inhibitor Tyvyt under review at the FDA. The application includes data from a China trial that showed a combination of Tyvyt, Lilly’s Alimta and platinum chemo could stave off tumor progression or death over chemotherapy alone.
For AZ, non-squamous NSCLC might be just what it could eventually reach for with the Imfinzi-treme-chemo pairing.
As POSEIDON lead investigator Melissa Johnson, M.D., noted during a prepared presentation Thursday, among patients with the squamous histology, progression-free survival (PFS) "and overall survival were poor across all treatment arms, with little separation of the curves for PFS or overall survival.”
In the squamous subgroup, Imfinzi, treme and chemo only managed to reduce the risk of death by 12% over chemo.
What’s more, the AZ therapy also showed some worrisome signs in other patient subgroups. Notably, women and Asian patients didn’t seem to experience any additional survival benefits from Imfinzi and treme.
The one upside? The efficacy of Imfinzi, treme and chemo didn’t seem to be bound by a patient’s PD-L1 expression level.
Still, with the mixed bag of data and a poor track record, AZ could face a limited FDA label and a hard time winning over market share in front-line NSCLC. Imfinzi is currently approved to treat stage 3 NSCLC and extensive-stage small cell lung cancer. In the first half of 2022, AZ plans to read out data from PEARL, an IMpower110 counterpart trial that evaluates Imfinzi monotherapy against chemo as front-line treatment for PD-L1-high patients.