FDA Schedules ODAC Meeting on Ramucirumab/Erlotinib in Frontline EGFR+ NSCLC

The FDA has scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for February 26, 2020, to discuss data supporting a supplemental biologics license application (sBLA) for intravenous ramucirumab (Cyramza) injection for use in combination with erlotinib (Tarceva) in the frontline treatment of patients with metastatic non—small cell lung cancer (NSCLC) whose tumors harbor EGFR Ex19del or Ex21 substitution mutations.¹

Data from the phase III RELAY trial showed that the addition of ramucirumab to erlotinib led to a 41% reduction in the risk of disease progression or death compared with erlotinib alone in the first-line treatment of patients with EGFR-mutated NSCLC.²

Specifically, at a median follow-up of 20.7 months, the median progression-free survival (PFS) by investigator assessment with the ramucirumab regimen versus erlotinib alone was 19.4 months (95% CI, 15.4-21.6) versus 12.4 months (95% CI, 11.0-13.5), respectively (HR, 0.59; 95% CI, 0.46-0.76; P <.0001).

This benefit was observed across several patient subgroups, including those with EGFR mutations. Those who harbored Ex19del experienced a median PFS of 19.6 months with the ramucirumab combination compared with 12.5 months with erlotinib (HR, 0.651; 95% CI, 0.469-0.903). Furthermore, those with Ex 21 L858R had a PFS of 19.4 months versus 11.2 months with the combination versus erlotinib alone, respectively.³

The multicenter, double-blind phase III trial enrolled a total of 449 patients with stage IV NSCLC who harbored either an EGFR Ex19del or Ex 21 L858R mutation and had an ECOG performance status of 0 to 1. Those with a known EGFR T790M mutation, those who received prior treatment with an EGFR TKI or chemotherapy, or those with brain metastases were not eligible to participate.

In the trial, patients were randomized to receive erlotinib at 150 mg daily in combination with either ramucirumab (n = 224) at 10 mg/kg every 2 weeks or placebo (n = 225). Patients received treatment until their disease progressed or they experienced unacceptable toxicity. The primary end point of the trial was PFS. Secondary end points included safety, overall survival (OS), overall response rate (ORR), and duration of response.

Although OS data for the trial are not yet mature, at the data cutoff, 37 OS events were reported in the ramucirumab combination arm compared with 42 events in the erlotinib-alone arm (HR, 0.832; 95% CI, 0.532-1.303). PFS2 data are also immature; however, 61 PFS2 events versus 79 PFS2 events were reported with ramucirumab versus erlotinib alone, respectively.

With regard to response, those who were administered the combination experienced an ORR of 76% compared with 75% of those who received erlotinib alone. The disease control rate with the ramucirumab combination was 95% versus 96% in those who did not receive the VEGFR-2 inhibitor. Lastly, the median duration of response in the ramucirumab arm versus the control arm was 18 months versus 11.1 months.

Investigators reported a higher percentage of treatment-emergent adverse events (TEAEs) with the ramucirumab regimen compared with erlotinib alone, at 72% versus 54%, respectively. Furthermore, the rate of serious TEAEs was also higher with ramucirumab compared with erlotinib alone, at 29% versus 21%, respectively. Thirteen percent of patients on the ramucirumab arm versus 11% of patients on the control arm discontinued treatment due to TEAEs; 85% versus 71% of patients required dose reductions due to these events and 1% versus 0% died due to these events, respectively.

Ramucirumab was granted an approval from the FDA in December 2014 for use in combination with docetaxel for the treatment of patients with metastatic NSCLC who progressed while on or following treatment with platinum-based chemotherapy.

The decision was based on the phase III REVEL trial, which had shown a 1.4-month improvement in OS with the combination versus the use of docetaxel alone.4 Specifically, the median OS with the ramucirumab regimen compared with docetaxel was 10.5 months versus 9.1 months, respectively (HR, 0.86; 95% CI, 0.75-0.98). This was the third indication that ramucirumab received in 2014.

In November 2014, the agent was also approved for use in combination with paclitaxel in the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. In April 2014, single-agent ramucirumab was granted approval for use in those with advanced gastric or GEJ adenocarcinoma that was unresponsive to, or had progressed following, frontline treatment with either a platinum- or fluoropyrimidine-containing chemotherapy.

References

1. February 26, 2020: Meeting of the Oncologic Drugs Advisory Committee Meeting announcement. US Food and Drug Administration; January 28, 2020. bit.ly/36FWEZk. Accessed January 29, 2020.
2. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5.
3. Nakagawa K, Garon EB, Seto T, et al. RELAY: a multinational, double-blind, randomized phase 3 study of erlotinib (erl) in combination with ramucirumab (ram) or placebo (pl) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15; abstr 9000). doi: 10.1200/JCO.2019.37.15_suppl.9000.
4. Larkins E, Scepura B, Blumenthal GM, et al. US Food and Drug Administration approval summary: ramucirumab for the treatment of metastatic non-small cell lung cancer following disease progression on or after platinum-based chemotherapy. Oncologist. 2015;20(11):1320-1325. doi: 10.1634/theoncologist.2015-0221.