Atezolizumab Monotherapy Improves Survival in Frontline PD-L1-High NSCLC

Sandra Horning, MD, chief medical officer and head of Global Product Development, Roche

Sandra Horning, MD

Single-agent atezolizumab (Tecentriq) extended overall survival (OS) compared with chemotherapy as a frontline treatment for patients with advanced nonsquamous and squamous non—small cell lung cancer (NSCLC) and high PD-L1 expression, according to topline findings from the phase III IMpower110 trial.

The statistically significant improvement in OS occurred in patients whose tumors did not harbor ALK or EGFR mutations. Patients in the comparator chemotherapy cohort received cisplatin or carboplatin at the investigator’s discretion in combination with either pemetrexed (Alimta; nonsquamous tumors) or gemcitabine (squamous tumors), followed by maintenance pemetrexed (nonsquamous) or best supportive care (squamous).

Patients’ PD-L1 status was determined by the SP142 assay test, with PD-L1 level stratifying patients into 1 of 3 categories: high (TC3/IC3-WT), medium (TC2/3/ IC2/3-WT), and low (TC1,2,3/IC1,2,3-WT). Genentech (Roche), the manufacturer of atezolizumab, reported in a press release that the trial is continuing to final analysis for the subgroups with lower PD-L1 levels. The company also noted that no new safety signals arose in the trial compared with previously reported data for atezolizumab.

“We are encouraged that Tecentriq monotherapy has shown a significant survival benefit over chemotherapy as an initial treatment in people with squamous or nonsquamous non—small cell lung cancer with high PD-L1 expression,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech (Roche), said in the press release. “These findings reinforce the potential of Tecentriq to play an important role in the treatment of multiple forms of lung cancer, and we look forward to discussing these data with health authorities.”

The open-label phase III IMpower110 trial accrued 572 patients (555 wild-type) with chemotherapy-naive advanced nonsquamous or squamous NSCLC without ALK or EGFR mutations, and randomized them to single-agent atezolizumab or chemotherapy. The primary endpoint was OS by PD-L1 subgroup, with secondary endpoints including investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). Genentech plans to share the data from the trial at an upcoming medical conference.

The FDA previously approved atezolizumab monotherapy in October 2016 for the treatment of patients with metastatic NSCLC who have progressed after a platinum-containing regimen and an FDA-approved targeted therapy for those patients harboring EGFR or ALK abnormalities.

The international, open-label randomized phase III OAK trial included 1225 patients with locally advanced or metastatic NSCLC—regardless of histology or PD-L1 status—who progressed during or after platinum-containing chemotherapy. Patients were randomized in a 1:1 ratio to 75 mg/m2 of intravenous docetaxel or 1200 mg of intravenous atezolizumab every 3 weeks.

Patient demographics were well balanced between the 2 arms at baseline. The median patients age was 64 years, 61% of patients were male, 18% had never smoked, and 25% had received 2 prior lines of therapy. Patients had an ECOG performance status of 0 (37%) or 1 (63%). Among patients randomized to docetaxel, 17% received immunotherapy as their next treatment.

The coprimary endpoints of the trial were OS in the entire study population and in a PD-L1—defined subgroup. Secondary endpoints included PFS, ORR, and DoR. The primary efficacy assessment included only the initial 850 randomized patients, and the secondary efficacy analysis will include data from all 1225 randomized patients.

In the intent to treat population (N = 850), the median OS was 13.8 months in the atezolizumab arm (n = 425) versus 9.6 months in the docetaxel arm (n = 425; HR, 0.74; 95% CI, 0.63-0.87; P = .0004). The PFS was 2.8 months versus 4 months (HR, 0.95), respectively. The ORR and DoR were 13.6% versus 13.4%, and 16.3 versus 6.2 months, respectively.

In nonsquamous patients, the median OS was 15.6 months in the atezolizumab group (n = 313) compared with 11.2 months in the control group (n = 315; HR, 0.73; 95% CI, 0.60-0.89). Among patients with squamous histology, the median OS was 8.9 months in the atezolizumab cohort (n = 112) versus 7.7 months on the docetaxel arm (n = 110; HR, 0.73; 95% CI, 0.54-0.98).

Regarding PD-L1 status, PD-L1—positive patients (TC1/2/3 or IC1/2/3) had expression on at least 1% of their tumor cells (TC) or tumor-infiltrating immune cells (IC). PD-L1 negative patients (TC0 or IC0) had less than 1% expression on their TC and IC.

Among the PD-L1—positive group, the median OS was 15.7 months in the atezolizumab arm (n = 241) compared with 10.3 months in the control arm (n = 222; HR, 0.74; 95% CI, 0.58-0.93; P = .0102). Among PD-L1—negative patients, the median OS was 12.6 months in the atezolizumab cohort (n = 180) versus 8.9 months in the docetaxel group (n = 199; HR, 0.75; 95% CI 0.59-0.96; P = .0205).

The safety profile with atezolizumab in the OAK trial was consistent with adverse event (AE) outcomes observed in previous studies of the PD-L1 inhibitor. AEs occurring more frequently in the atezolizumab arm included musculoskeletal pain (11% vs 4% with docetaxel) and pruritus (8% vs 3%).

The rate of grade 3/4 AEs was lower in the atezolizumab arm versus the control arm at 15% versus 43%, respectively. No treatment-related deaths occurred in the atezolizumab cohort compared with 1 in the docetaxel arm.

In the frontline NSCLC setting, bevacizumab is approved for use in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the treatment of patients with metastatic nonsquamous NSCLC. The indication excludes patients with EGFR/ALK aberrations.

References

1. Genentech’s Tecentriq (atezolizumab) as a first-line monotherapy helped certain people with advanced non-small cell lung cancer live longer compared with chemotherapy. Genentech. Published September 12, 2019. Accessed September 12, 2019. https://bit.ly/2kwqgGN.
2. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA44.

The approval was based on multiple clinical trials, the largest being the phase III OAK trial, which was presented at the 2016 ESMO Congress.¹ Data from the study available at the time of the approval showed that atezolizumab reduced the risk of death by 26% compared with docetaxel in patients with advanced NSCLC following the failure of platinum-based chemotherapy. The median OS was improved by 4.2 months with the PD-L1 inhibitor versus chemotherapy. The survival benefit with atezolizumab was observed regardless of PD-L1 status or histology.