Bevacizumab/Erlotinib Adds Another Option to Frontline EGFR+ NSCLC

Findings from the phase III NEJ026 study, presented at the 2018 ASCO Annual Meeting and now published in Lancet Oncology,¹ showed that adding bevacizumab (Avastin) to erlotinib (Tarceva) significantly improved progression-free survival (PFS) versus erlotinib alone in patients with EGFR-positive, advanced nonsquamous non—small cell lung cancer (NSCLC).

Data from an interim analysis of NEJ026 showed that the bevacizumab combination reduced the risk of disease progression or death by nearly 40% compared with erlotinib monotherapy. At a median follow-up of 12.4 months, the median PFS was 16.9 months (95% CI, 14.2-21.0) versus 13.3 months (95% CI, 11.1-15.3), respectively (HR, 0.605; 95% CI, 0.417-0.877; P = .016).

“These results suggest that combination therapy with bevacizumab and erlotinib has the potential to become a standard treatment for patients with EGFR-positive NSCLC if the overall survival data and quality of life analyses are favorable,” lead author Haruhiro Saito, MD, Kanagawa Cancer Center, Yokohama, Japan, and coauthors wrote.

In the phase III FLAURA study, the third-generation EGFR TKI osimertinib (Tagrisso) reduced the risk of progression or death by 54% versus standard therapy with either erlotinib or gefitinib.² The median PFS was 18.9 months (95% CI, 15.2-21.4) with osimertinib compared with 10.2 months (95% CI, 9.6-11.1) for standard treatment (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

The phase III NEJ009 trial showed that adding carboplatin and pemetrexed chemotherapy to gefitinib (GCP regimen) improved median PFS and overall survival (OS) versus gefitinib alone.³ The median PFS was 20.9 months (95% CI, 18.0-24.2) with GCP compared with 11.2 months (95% CI, 9.0-13.4) with gemcitabine (HR, 0.493; 95% CI, 0.390-0.623; P <.001). The median OS was 52.2 versus 38.8 months, respectively (HR, 0.695; P = .013).

Commenting on the evolving options available for frontline EGFR-positive NSCLC, Saito et al wrote, “Since toxicity profiles and baseline parameters for patients vary widely, the optimum regimen (erlotinib and bevacizumab combination therapy, osimertinib treatment, or a combination of TKI and chemotherapy) should be considered on a case-by-case basis.”

The open-label phase III NEJ026 study enrolled patients with EGFR-positive advanced nonsquamous NSCLC at 69 centers in Japan. Patient characteristics were well balanced between the arms. In the combination arm, the median patient age was 67 years (range, 61-73), 63% of patients were women, all patients had an ECOG performance status of 0 or 1, and 32% of patients had CNS metastases.

Patients were randomized to receive 150 mg of oral erlotinib daily either alone (n = 114) or in combination with bevacizumab at 15 mg/kg IV every 21 days (n = 114). The primary endpoint was PFS, with secondary endpoints including OS, objective response rate (ORR), duration of response, and safety.

There were 112 patients in each arm included in the efficacy analysis. The ORR was 72% with the addition of bevacizumab versus 66% with erlotinib alone. The complete and partial response rates were 7% versus 4% and 65% versus 63%, respectively. Twenty-two percent of patients in the combination arm had stable disease compared with 30% of patients in the erlotinib group.

Grade ≥3 adverse events (AEs) occurred in 88% of the bevacizumab/erlotinib arm compared with 46% in the control arm. The most common grade 3 AEs in the combination group were rash (21% vs 21% in the erlotinib arm) and hypertension (23% vs 1%, respectively). The only grade 4 AE occurring in more than 1 patient receiving the combination was increased aminotransferase (n = 3). No grade 4 AEs occurred in more than 1 patient in the control arm. There were no deaths related to treatment in the study.

Regarding next steps, Saito et al wrote, “Two other phase 3 clinical trials in patients with EGFR-positive NSCLC—BEVERLY (NCT02633189) and Artemis (NCT02759614)&mdash;which are testing the addition of bevacizumab to erlotinib, are ongoing. The results of these studies are awaited to confirm the preliminary data of this trial on the efficacy and safety of bevacizumab plus erlotinib in this setting.”

Beyond the 3 frontline options in EGFR-positive NSCLC described above, yet another option that has emerged in the space is the second-generation EGFR TKI dacomitinib (Vizimpro). In September 2018, the FDA approve dacomitinib for the frontline treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations.

The approval was based on the phase III ARCHER 1050 trial, in which the median PFS was 14.7 months with dacomitinib compared with 9.2 months with gefitinib (HR, 0.59; 95% CI, 0.47-0.74; P <.0001).⁴ The median OS was 34.1 versus 26.8 months, respectively.⁵

In an accompanying editorial to the NEJ026 paper, James Chih-Hsin Yang, department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University, commented on the current state and next steps in this crowded treatment paradigm.⁶

“The number of possible combinations and treatment sequences of EGFR TKIs, chemotherapy, bevacizumab, or anti—PD-1/PD-L1 inhibitors complicate recommendations for first-line and second-line treatment in patients with NSCLC and EGFR mutations. At present, no biomarkers exist to enable the selection of the optimum treatment order for patients. Future studies might provide more evidence about treatment strategies.”

References

1. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial [published April 8, 2019]. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(19)30035-X.
2. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.
3. Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). American Society of Clinical Oncology Meeting; Chicago, IL; June 1—5, 2018. 9005.
4. Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial. J Clin Oncol. 2017;35(suppl; abstr LBA9007).
5. Mok T, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study comparing dacomitinib with gefitinib in patients with advanced non-small cell lung cancer harboring EGFR-activating mutations. J Clin Oncol. 2018;36(suppl; abstr 9004).
6. Yang JC-H. Bevacizumab in EGFR-positive NSCLC: time to change first-line treatment? [published April 8, 2019]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30085-3.

The NEJ026 study joins other recent trials in which novel approaches have improved outcomes over monotherapy with the first-generation TKIs gefitinib (Iressa) and erlotinib for the frontline treatment of patients with EGFR-positive NSCLC.