Atezolizumab Improves Survival in High PD-L1 Expressing NSCLC

David R. Spigel, MD

In an interim survival analysis of the phase III Impower 110 study, atezolizumab (Tecentriq) monotherapy improved overall survival (OS) compared with platinum-based chemotherapy as a first-line treatment of patients with wild-type non—small cell lung cancer (NSCLC) who had ≥50% expression of PD-L1 on tumor cells (TC3) or ≥10% expression on tumor-infiltrating immune cells (IC3).

At a median follow-up of 15.7 months (range, 0-35), median OS was 20.2 months (95% CI, 16.5-not evaluable) in patients randomized to atezolizumab compared with 13.1 months (95% CI, 7.4-16.5) in those randomized to platinum-based chemotherapy (HR, 0.59; 95% CI, 0.40-0.89; P = .0106), reported David R. Spigel, MD, at the 2019 ESMO Congress.

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

“Atezolizumab represents a promising first-line treatment option in patients with PD-L1 high NSCLC,” said Spigel, chief scientific officer, Sarah Cannon Research Institute in Nashville, Tennessee. “In the TC3 or IC3 wild-type population, atezolizumab showed meaningful improvement in progression-free survival [PFS], objective response rate [ORR], and duration of response [DOR] vs chemotherapy.”

Median PFS was 8.1 months (95% CI, 6.8-11.0) in the atezolizumab arm and 5.0 months (95% CI, 4.2-5.7) in the chemotherapy arm (HR, 0.63; 95% CI, 0.45-0.88; P = .007) in the TC3 or IC 3 wild-type population; the confirmed ORR was 38.3% vs. 28.6%, respectively; and the median DOR was not reached versus 6.7 months, respectively.

IMpower110 evaluated atezolizumab as first-line treatment in PD-L1—selected patients with advanced NSCLC, independent of tumor histology. It enrolled 572 patients with chemotherapy-naïve stage IV nonsquamous or squamous NSCLC with PD-L1 expression ≥1% on tumor cells (TC) or immune cells (IC). Patients were randomized 1:1 to receive atezolizumab, 1200 mg every 3 weeks (arm A), or 4 or 6 cycles of platinum-based chemotherapy (arm B).

Patients in arm B with nonsquamous histology received cisplatin, 75 mg/m², or carboplatin, area under the curve (AUC) 6, plus pemetrexed, 500 mg/m² intravenously every 3 weeks. Patients in arm B with squamous histology received cisplatin, 75 mg/m², plus gemcitabine, 1250 mg/m², or carboplatin, AUC 5, plus gemcitabine, 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.

Excluded were patients with EGFR-positive or ALK-positive NSCLC, leaving 554 patients (277 in each arm) who were evaluated.

The primary endpoint of OS was tested hierarchically in wild-type 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 wild type. The secondary endpoint of PFS would only be formally tested if the primary endpoint was positive among all 3 TC/IC cohorts.

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 wild type, compared with 35.4% 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). However, “because this didn’t cross the prespecified alpha boundary, the P value was not statistically significant, but the benefit is clearly in favor of atezolizumab,” said Spigel. OS also favored atezolizumab in the TC 1/2/3 or IC 1/2/3 wild-type population but was not significant (HR, 0.83; 95% CI, 0.65-1.07; P = .1481).

Some 29.6% in the atezolizumab arm and 49.5% in the chemotherapy had at least 1 subsequent cancer therapy, and 28.9% in the chemotherapy arm ultimately received a form of immunotherapy.

In the TC3 or IC3 wild-type 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 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 statistical significance could not be tested.

The safety profile favored arm A, with no new or unexpected safety signals seen. Treatment-related adverse events (TRAEs) occurred in 60.5% (arm A) and 85.2% (arm B), and grade 3/4 TRAEs occurred in 12.9% and 44.1%, respectively. “An important question that clinicians want to know is how many patients require steroids, and that number is about 8% [in the atezolizumab arm],” Spigel said.

Additional biomarker analyses will be presented at upcoming conferences, including tumor mutational burden in the blood, he said.

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. Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA78.

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