AstraZeneca Hopes Imfinzi Breakthrough Get Can Burn Off MYSTIC Failure
Executive Summary
Imfinzi becomes first cancer immunotherapy designated a breakthrough therapy for non-metastatic non-small cell lung cancer patients who have not progressed after platinum-based chemoradiation therapy, just days after announcing a missed primary endpoint in the first-line MYSTIC trial in metastatic NSCLC.
A new breakthrough therapy designation (BTD) for AstraZeneca PLC's Imfinzi (durvalumab) signals FDA's confidence in the promise of the agent in non-metastatic non-small cell lung cancer, a setting earlier in the disease course than the metastatic NSCLC indications FDA has so far granted to immunotherapies.
The BTD is a welcome counterpoint to the disappointing results from the Phase III MYSTIC trial as first-line treatment for metastatic NSCLC, a more competitive (and lucrative) disease setting for the PD-1/L1 inhibitor class.
The new BTD is for Imfinzi treatment of patients with locally-advanced, unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation therapy, AstraZeneca reported July 31. The designation is based on interim data from another Phase III trial, the PACIFIC study.
MYSTIC Miss In First-Line Metastatic NSCLC
While the MYSTIC trial is ongoing, AstraZeneca's July 27 announcement that the study had failed to meet one of its co-primary endpoints was seen as a huge blow to Imfinzi's prospects in NSCLC. (Also see "MYSTIC Misses: Devastation For AstraZeneca As Imfinzi Fails PFS Endpoint In NSCLC" - Scrip, 27 Jul, 2017.) Imfinzi is the newest of the five PD-1/L1 inhibitors approved by FDA, receiving accelerated approval for locally advanced or metastatic urothelial carcinoma after platinum therapy on May 1, 2017; the AZ antibody holds a BTD in that setting for patients who are PD-L1-positive.
MYSTIC is a large undertaking, with an enrollment of more than 1,100 previously untreated Stage IV NSCLC patients randomized to three arms: durvalumab in combination with AZ's CTLA-4 inhibitor candidate tremelimumab, durvalumab monotherapy, or standard of care platinum-based chemotherapy. The trial's co-primary endpoints compare the durvalumab combination against standard of care for progression-free survival (PFS) and overall survival (OS) and compare durvalumab monotherapy to SOC for OS.
The Imfinzi/tremelimumab arm failed to improve PFS more than standard therapy, AstraZeneca reported.
The Imfinzi monotherapy arm would not have met a pre-specified threshold of PFS benefit over standard of care in previously untreated metastatic NSCLC, the company added, although the company noted that the comparison was not formally tested.
The top-line MYSTIC findings are "disappointing," AstraZeneca Chief Medical Officer Sean Bohen acknowledged, but the company emphasized that the trial will continue to assess OS for both Imfinzi monotherapy and the Imfinzi/tremelimumab combo.
AstraZeneca is not the first immunotherapy sponsor to be disappointed by Phase III results as first-line metastatic NSCLC therapy. Bristol-Myers Squibb Co.'s CheckMate 26 trial of Opdivo (nivolumab) failed to meet its primary endpoint of PFS compared with chemotherapy in patients with at least 5% PD-L1 expression, and also failed to show an effect at higher PD-L1 thresholds. (Also see "'Total Disaster' In First-Line Lung Cancer For BMS's Opdivo" - Scrip, 10 Oct, 2016.)
PACIFIC Supports BTD In Non-Metastatic NSCLC
Imfinzi's new BTD marks the earliest of stage cancer for which an immunotherapy has received breakthrough status. As with most novel oncology development, sponsors have targeted sicker patients first.
"Imfinzi is the first immuno-oncology medicine to show a clinically significant benefit in this earlier, non-metastatic setting," Bohen said. Indeed, Imfinzi could be the first medicine to make that claim in NSCLC; he noted that the only current option for patients who have not progressed following chemoradiation is active monitoring.
The BTD is based on interim results from the PACIFIC trial, a Phase III placebo-controlled trial of Imfinzi as sequential treatment in patients with locally advanced unresectable (Stage III) NSCLC who had not progressed following standard platinum-based chemotherapy concurrent with radiation therapy.
The PACIFIC data created a stir in May, when a planned interim analysis found that the trial had already met a primary endpoint of progression-free survival (PFS). (Also see "AstraZeneca's Imfinzi Steals March Into Untapped IO Lung Cancer Territory" - Scrip, 12 May, 2017.)
PACIFIC continues to follow patients for its co-primary endpoint of OS. The 713-patient trial, which started in 2014, randomized patients to Imfinzi or placebo for a maximum of 12 months.