Roche’s Tecentriq made history last year as the first PD-1/L1 agent to win an approval in triple-negative breast cancer. But trials with seemingly contradictory results put its potential role in the hard-to-treat disease into question, especially as Merck & Co. makes inroads into the same field with its formidable Keytruda.
In four Tecentriq-chemo combo trials in TNBC patients, presented at the European Society of Medical Oncology (ESMO) virtual meeting Saturday, the results differed in important ways.
In the IMpassion031 trial in early breast cancer patients ahead of surgery, a combination of Tecentriq and chemo obliterated signs of cancer in more patients than did chemo alone, regardless of their tumors’ PD-L1 expression status.
The 16.5% absolute improvement in pathologic complete response (pCR) in the Tecentriq group, on top of the 41.1% for solo chemo, was both statistically significant and clinically meaningful, Roche said.
Surprisingly, on the trial’s co-primary endpoint—which zeroed in on PD-L1-positive patients, a subgroup who normally respond better to checkpoint inhibition—the difference wasn't statistically significant, even though it was a numerically larger 19.5%.
Let’s not forget that, in the phase 3 IMpassion130 trial in metastatic patients that earned Tecentriq its first-in-class FDA nod last year, the benefit was more pronounced in the PD-L1-positive group—so much so that its eventual FDA go-ahead covered only that patient population.
Final analysis of that study presented at ESMO showed that adding the PD-L1 inhibitor to Celgene’s Abraxane—protein-bound paclitaxel—cut the risk of death by only 13% in all-comer patients with previously untreated locally advanced or metastatic TNBC. The magnitude of risk reduction widened to 33% in the PD-L1-positive group.
The Tecentriq-Abraxane combo helped PD-L1-positive patients live 7.5 months longer than did solo chemo, an improvement that investigators labeled as “clinically meaningful.”
Roche’s phase 3 IMpassion031 trial in the presurgery neoadjuvant setting also came in the wake of an investigator-sponsored NeoTRIPaPDL1 trial flop in the same neoadjuvant setting. Data presented at last year’s San Antonio Breast Cancer Symposium found Tecentiq-chemo failed to significantly improve pCR in both the all-trialed population and in PD-L1-positive patients.
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Cross-trial comparisons can be problematic because of differences in dosing, patient characteristics and more. For example, the chemotherapy and dosing cycles in IMpassion031 and NeoTRIPaPDL1 were different. Patients in IMpassion031 continued to receive unblinded Tecentriq after surgery, while NeoTRIPaPDL1 only gave patients chemo postsurgery, which might help explain the higher response rate in the Roche trial.
Updating at ESMO, investigators of NeoTRIPaPDL1 showed that an imbalance in baseline tumor-infiltrating immune cells—which are known indicators of responsiveness to PD-1/L1 therapies—might have resulted in smaller differences of pCR.
But Tecentriq also posted an outright failure in the front-line metastatic setting. In the IMpassion131 trial—which paired the IO med with the original paclitaxel formulation, rather than Abraxane—Tecentriq didn’t help stall cancer progression longer than solo chemo.
In fact, patients who got the Tecentriq-paclitaxel combo didn't live as long as those in the chemo-only group. The pairing increased the risk of death by 12% and 11% in PD-L1-positive and intent-to-treat populations, respectively, according to data presented at ESMO.
Researchers have yet to pinpoint potential reasons for that dramatic flop in contrast with the benefit—at least in the PD-L1-positive group—in IMpassion130, but the failure already got the FDA’s attention.
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A few days ago, the agency warned physicians not to substitute Abraxane, or paclitaxel protein-bound, with the original paclitaxel in clinical practice.
And while Tecentriq confuses industry watchers and physicians with these mixed trial results, Merck’s Keytruda might swoop in. Keytruda, given alongside chemo, pared down the risk of disease progression or death by 35% against solo chemo in patients with high levels of PD-L1 in the Keynote-355 trial. The Merck drug also has a neoadjuvant win under its belt with Keynote-522.
What’s more, Merck just penned a deal for Seattle Genetics’ experimental anti-LIV-1 antibody-drug conjugate, ladiratuzumab vedotin, which is being paired with Keytruda in metastatic TNBC trials.
The next question could be, is chemo combo still the way to go for PD-1/L1 inhibitors in TNBC? We will see.