FDA Grants Priority Review to Frontline Atezolizumab for Advanced PD-L1-High NSCLC

Levi Garraway, MD, PhD

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for single-agent atezolizumab (Tecentriq) as a frontline treatment for patients with advanced nonsquamous or squamous non—small cell lung cancer (NSCLC) without EGFR or ALK mutations who have high PD-L1 expression on tumor cells or tumor-infiltrating immune cells, defined as TC3/IC3 wild-type (WT).¹

The application is based on findings from the phase III IMpower110 trial, which showed that atezolizumab monotherapy demonstrated a 7.1-month improvement in overall survival (OS) versus chemotherapy, with a median OS of 20.2 months and 13.1 months, respectively (HR, 0.595; 95% CI, 0.398-0.890; P = .0106) in patients with NSCLC and high PD-L1 expression.²

The safety results for atezolizumab were consistent with previously reported studies with the PD-L1 inhibitor; no new safety signals were identified. Moreover, grade 3/4 treatment-related adverse events (TRAEs) were reported in 12.9% of patients on the atezolizumab arm compared with 44.1% of those who received chemotherapy.

Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sBLA by June 19, 2020.

“In the IMpower110 study, Tecentriq alone demonstrated a significant improvement in overall survival compared with chemotherapy for people newly diagnosed with certain types of advanced non—small cell lung cancer,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, of Genentech (Roche), the developer of atezolizumab, stated in a press release. “We are working closely with the FDA to bring this chemotherapy-free option to these patients as quickly as possible.”

In the open-label, randomized, phase III IMpower110 study, investigators randomized 572 PD-L1—selected, chemotherapy-naïve patients with advanced nonsquamous or squamous NSCLC without ALK or EGFR mutations 1:1 to receive single-agent atezolizumab (arm A) or cisplatin or carboplatin plus pemetrexed or gemcitabine (arm B). Atezolizumab was administered until loss of clinical benefit, unacceptable toxicity or death, or per investigator discretion.

For nonsquamous disease, chemotherapy regimens consisted of cisplatin at 75 mg/m² or carboplatin area under the curve (AUC) 6, plus pemetrexed at 500 mg/m² intravenously every 3 weeks. Patients with squamous histology who were on the chemotherapy arm received cisplatin at 75 mg/m² plus gemcitabine at 1250 mg/m², or carboplatin AUC 5 plus gemcitabine at 1000 mg/m² intravenously every 3 weeks.

Maintenance therapy consisted of atezolizumab in arm A and pemetrexed (nonsquamous) or best supportive care (squamous) in arm B. No crossover was permitted.

The primary endpoint is OS by PD-L1 subgroup (TC3/IC3-WT; TC2/3/ IC2/3-WT; and TC1/2/ 3/IC1/2/3-WT), as determined by the SP142 assay. Key secondary endpoints include investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR).

The primary endpoint of OS was tested hierarchically in WT patients (TC3 or IC3, then TC2/3 or IC2/3, then TC1/2/3 or IC1/2/3); a total of 205 patients were TC3 or IC3 WT. The secondary endpoint of PFS would only be formally tested if the primary endpoint was positive among all 3 TC/IC cohorts.

The OS testing boundary was not crossed in the TC2/3 or IC2/3 WT population, so OS was not formally tested in this population as well as in the TC1/2/3 and IC1/2/3 populations.

Baseline characteristics were well balanced between the arms, including in the TC3 or IC3 subset. About half of the patients overall were <65 years old, about 70% were male, >80% were white, and 13% never used tobacco. Approximately 70% in both arms had nonsquamous histology.

In arm A, 38.6% of patients were TC3 or IC3 WT, compared with 35.4% of patients in arm B. Some 59.9% in arm A and 58.5% in arm B were TC2/3 or IC2/3 (≥5% expression on tumor cells or immune cells) wild type.

In the TC3/IC3 wild-type population, 76.3% in arm A and 70.1% in arm B were alive at 6 months, and the 12-month OS rates were 64.9% and 50.6%, respectively. Subset analysis showed a consistent benefit on OS favoring atezolizumab in all subgroups with TC3 or IC3 wild type, except for in those who had never used tobacco.

In the TC 2/3 or IC 2/3 wild-type subgroup, median OS was 18.2 months (95% CI, 13.3-not evaluable) in the atezolizumab arm versus 14.9 months (95% CI, 10.8-16.6) in the chemotherapy arm (HR, 0.72; 95% CI, 0.52-0.99; P = .0416). OS also favored atezolizumab in the TC 1/2/3 or IC 1/2/3 wild-type population but was not found to be significant (HR, 0.83; 95% CI, 0.65-1.07; P = .1481).

Additionally, 29.6% of patients in the atezolizumab arm and 49.5% in the chemotherapy had ≥1 subsequent cancer therapy, and 28.9% in the chemotherapy arm ultimately received a form of immunotherapy.

In the TC3 or IC3 WT population, the 6-month PFS rate was 59.8% in arm A and 38.3% in arm B, and at 12 months, 36.9% in arm A were without disease progression compared with 21.6% in arm B. PFS was numerically superior in the atezolizumab arm in the TC2/3 or IC2/3 and TC1/2/3 or IC1/2/3 subgroups, although the statistical significance could not be tested.

Regarding safety, TRAEs occurred in 60.5% (arm A) and 85.2% (arm B) of patients.

A biomarker analysis of the IMpower110 trial was presented during the 2019 ESMO Immuno-Oncology Congress. Results showed that PD-L1—high status, determined via 3 separate immunohistochemistry (IHC) assays, and blood tumor mutational burden (bTMB) strongly favored atezolizumab over platinum-based chemotherapy and supports the PD-L1 inhibitor as a first-line treatment option in patients with advanced NSCLC.³

References

1. FDA grants priority review to Roche’s Tecentriq monotherapy as first-line treatment of certain people with advanced non-small cell lung cancer [news release]: Basel, Switzerland. Genentech (Roche). Published February 19, 2020. https://bit.ly/2SHbbjS. Accessed February 19, 2020.
2. Spigel DR, De Marinis F, Giaccone G, et al. IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1—selected NSCLC. Ann Oncol. 2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.
3. Herbst RS, Marinis FD, Giaccone G, et al. Clinical efficacy of atezolizumab in biomarker subgroups by SP142, SP263 and 22C3 PD-L1 immunohistochemistry assays and by blood tumour mutational burden: results from the IMpower110 study. Ann Oncol. 2019;30(suppl_11):mdz453. doi: 10.1093/annonc/mdz453.