EU Panel Backs Frontline Atezolizumab Regimen in NSCLC

Sandra Horning, MD

The European Medicine’s Agency Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the frontline combination of atezolizumab (Tecentriq), bevacizumab (Avastin), paclitaxel, and carboplatin for the first-line treatment of patients with metastatic, nonsquamous non—small cell lung cancer (NSCLC).¹

For patients with EGFR or ALK molecular abnormalities, the 4-drug regimen should be indicated only after progression on appropriate targeted therapies.

The recommendation is based on data from the phase III IMpower150 study, which showed that the combination of atezolizumab, bevacizumab, and chemotherapy improved overall survival (OS) versus bevacizumab plus chemotherapy alone. The median OS was 19.8 months with the atezolizumab regimen versus 14.9 months with bevacizumab/carboplatin/paclitaxel (HR, 0.76; 95% CI, 0.63-0.93; P = .006) in the intent-to-treat population. Moreover, the safety profile of the atezolizumab combination was consistent with what has been reported in previous studies.

“We are pleased to receive a positive opinion from the CHMP for this Tecentriq-based combination, which represents a significant step towards bringing a new treatment option to people across Europe with advanced, nonsquamous non-small cell lung cancer,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, Roche. “The IMpower150 study, on which this opinion is based, demonstrated an overall survival benefit, including those in key populations such as people with EGFR- or ALK-positive mutations or liver metastases.”

In the multicenter, open-label, controlled, randomized phase III IMpower150 study, researchers evaluated the efficacy and safety of atezolizumab in combination with carboplatin and paclitaxel with or without bevacizumab in 1202 patients with stage IV or recurrent metastatic nonsquamous NSCLC who were not previously treated with chemotherapy for their advanced disease.

Patients were randomized evenly to receive atezolizumab, carboplatin, and paclitaxel ([ACP] arm A; n = 402), atezolizumab, bevacizumab, and chemotherapy ([ABCP] arm B; n = 400), or bevacizumab and chemotherapy ([BCP] arm C; n = 400).

In the investigational arms, atezolizumab was administered at 1200 mg intravenously every 3 weeks and bevacizumab was given at 15 mg/kg. In each arm, carboplatin and paclitaxel were given on day 1 of each cycle for 4 to 6 cycles. In arm A, maintenance therapy was given with atezolizumab alone and in arm B patients received maintenance therapy with the combination of bevacizumab and atezolizumab. In arm C, maintenance was given with bevacizumab alone.

The trial was designed to exclude data for patients with EGFR/ALK-mutated NSCLC from the co-primary endpoints of OS and progression-free survival (PFS). Approximately 13% of the trials' patients were EGFR or ALK-positive. Prior to study entry, these patients had received at least 1 prior EGFR tyrosine kinase inhibitor.

Additional results showed that ABCP reduced the risk of disease progression or death by 41% compared with BCP (HR, 0.59; 95% CI, 0.50-0.69; P <.0001) in the overall ITT population. Moreover, the overall response rate (ORR) was 56.4% (95% CI, 51.4-61.4) with ABCP versus 40.2% (95% CI, 35.3-45.2) for those on BCP. The responses on the ABCP arm consisted of a 2.8% complete response (CR) rate and a 53.7% partial response (PR) rate. The median duration of response (DOR) was 11.5 months (95% CI, 8.9-15.7) for ABCP and 6.0 months (95% CI, 5.5-6.9) for BCP.

Moreover, in patients with liver metastases, there was a 46% reduction in the risk of death with ABCP compared with BCP (HR, 0.54; 95% CI, 0.33-0.88) and a 46% reduction in the risk of death for patients with EGFR/ALK-mutated NSCLC (HR, 0.54; 95% CI, 0.29-1.03).^2,3

In the wild-type intent-to-treat population, the 18-month PFS rate was 27% with ABCP and 8% for BCP. The 18-month OS rate was 53% with ABCP compared with 41% for BCP. The ORR with ABCP was 55% compared with 42% for BCP, with CRs rates of 4% and 1%, respectively. The DOR was 10.8 months with ABCP, 6.5 months with BCP, and 9.5 months with ACP.

In patients with liver metastases in the wild-type analysis, the median OS with ABCP was 13.2 month compared with 9.1 months with BCP (HR, 0.54). Patients without liver metastases had a median OS of 19.8 versus 16.7 months for ABCP and BCP, respectively (HR, 0.83). The median OS in patients with EGFR/ALK mutations only was not evaluable with ABCP versus 17.5 months for BCP (HR, 0.54).

Favorable efficacy was seen with the ABCP combination compared with BCP across PD-L1 expression levels. In those with PD-L1 high expression (tumor cells [TC] 3 or immune cells [IC] 3; n = 136), the median OS was 25.2 months with ABCP compared with 15.0 months for BCP (HR, 0.70; 95% CI, 0.43-1.13). The ORR in this group was 69% with ABCP compared with 62% with ACP and 49% with BCP. The DOR with ABCP in this group was 22.1 months compared with 12.2 months with ACP and 7.0 months for BCP.

In the PD-L1—low group (TC1/2 or IC1/2; n = 226), the median OS was 20.3 versus 16.4 months for ABCP and BCP, respectively (HR, 0.80; 95% CI, 0.55-1.15). In the PD-L1–negative group (TC0/IC0; n = 339), the median OS was 17.1 versus 14.1 months for ABCP and BCP, respectively (HR, 0.82; 95% CI, 0.62-1.08).

Regarding safety, the most common adverse events occurring in ≥20% of patients receiving ABCP were asthenia (50%), alopecia (48%), nausea (39%), diarrhea (32%), constipation (30%), decreased appetite (29%), arthralgia (26%), hypertension (25%), and peripheral neuropathy (24%).

The FDA approved the frontline regimen of atezolizumab, bevacizumab, carboplatin, and paclitaxel for this patient population in December 2018.

References

1. CHMP recommends EU approval of Roche’s Tecentriq in combination with Avastin and chemotherapy as an initial treatment for lung cancer. Genentech (Roche). Published February 1, 2019. https://bit.ly/2S26KRH. Accessed February 1, 2019.
2. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36 (suppl; abstr 9002). doi: 10.1200/JCO.2018.36.15_suppl.9002.
3. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.