Atezolizumab Improves Survival in High PD-L1 Expressing NSCLC

Atezolizumab (Tecentriq) monotherapy improved overall survival compared with platinum-based chemotherapy as a first-line treatment of certain patients with wild-type non–small cell lung cancer.

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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