The FDA's Oncologic Drugs Advisory Committee voted 6 to 5 in favor of intravenous ramucirumab injection for use in combination with erlotinib as a frontline treatment for patients with metastatic non–small cell lung cancer whose tumors harbor EGFR exon 19 deletions (Ex19del) or exon 21 (L858R) substitution mutations.
The FDA's Oncologic Drugs Advisory Committee voted 6 to 5 in favor of intravenous ramucirumab (Cyramza) injection for use in combination with erlotinib (Tarceva) as a frontline treatment for patients with metastatic non—small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions (Ex19del) or exon 21 (L858R) substitution mutations.1
The FDA scheduled an Oncologic Drugs Advisory Committee hearing to discuss data supporting a supplemental biologics license application (sBLA) for the combination in this setting, which was based on findings from the phase III RELAY trial.2 In the study, results 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.
At a median follow-up of 20.7 months, the investigator-assessed median progression-free survival (PFS) 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).
The committee sought to discuss whether the risk-benefit profile of ramucirumab/erlotinib can be adequately assessed without overall survival (OS) data, and whether the improvement seen in PFS is clinically meaningful in the context of additive toxicity.3
Philip C. Hoffman, MD, chairperson of the ODAC committee and who voted in favor of the application, summarized the committee’s opinions on moving forward with the SBLA during the hearing.
"The people that voted ‘Yes’ to summarize, felt that this was a feasible combination to add to our armamentarium, that the [progression-free survival] was indeed a worthwhile difference," said Hoffman. "Again, it's another weapon to have available and the safety appears to be tolerable. The people who had voted 'No' are concerned about the lack, at this point, of OS information and particulary that survival might be reduced with this combination, [has] yet to be determined. There does not appear to be an improvement in quality of life, and there is significant toxicity for some patients—and that made it not something that they could approve."
In the multicenter, double-blind, phase III RELAY trial, investigators enrolled 449 patients with stage IV NSCLC who harbored either an EGFR Ex19del or exon 21 L858R mutation and had an ECOG performance status of 0 to 1. Those with a known EGFR T790M mutation, received prior treatment with an EGFR TKI or chemotherapy, or had brain metastases were ineligible for enrollment.
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 endpoint was PFS; secondary endpoints included safety, OS) overall response rate (ORR), and duration of response (DOR).
The PFS 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.
At an earlier data cutoff of January 23, 2019, 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 were also immature; however, 61 PFS2 events versus 79 PFS2 events were reported with ramucirumab versus erlotinib alone, respectively.
At the FDA’s request, Eli Lilly and Company, the developer of ramucirumab, provider the agency with an updated OS analysis. With longer follow-up at a data cutoff date of December 31, 2019, the updated hazard ratio for OS was 0.92 (95% CI, 0.65-1.32). The agency added that given the upper limit of the confidence interval of 1.3, the results suggest a potential detrimental impact on survival in the combination arm, as well as safety concerns.
“While the first-line treatment of patients with EGFR-positive NSCLC remains an unmet medical need, there are therapies currently approved for which an improvement in OS has been observed when compared to first-generation EGFR TKI,” the FDA noted in the document.
Additionally, the ORR was 76% in the combination arm compared with 75% in the erlotinib/placebo arm. Moreover, the disease control rate with the ramucirumab combination was 95% versus 96% in those who did not receive the VEGFR-2 inhibitor. The median DOR in the ramucirumab arm versus the control arm was 18 months versus 11.1 months.
The panel also sought to highlight the clinically meaningfulness of the PFS benefit in the context of additive toxicity. In the combination arm in RELAY, the rate of grade ≥3 adverse events (AEs) was 72% compared with 54% for erlotinib alone; the rate of serious AEs was 29% and 21%, respectively. AEs of special interest included bleeding/hemorrhage, hypertension, and proteinuria, and higher incidence of severe infections occurred more frequently in the combination arm.
Investigators also reported that 13% of patients on the ramucirumab/erlotinib arm versus 11% of those 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.
Moreover, more AE-related deaths due to adverse events on study or within 30 days of treatment discontinuation were reported in the ramucirumab plus erlotinib arm (n = 6) compared with 0 in the erlotinib/placebo arm. Of the 6 deaths on the combination arm, the FDA considered 1 death, which was attributed to hemothorax, to be treatment-related. A second death, which occurred from encephalitis influenza, was potentially related to treatment, the agency noted.
Eva Szabo, MD, chief of the Lung and Upper Aerodigestive Cancer Research Group at the Division of Cancer Prevention, National Cancer Institute, voted in favor of the combination as a treatment for this patient population.
"I voted 'Yes,' and the reason I voted ‘Yes’ was that, although the side effect profile is more severe than erlotinib alone and probably other TKIs, I was convinced by [Dr.] Richard Pazdur’s framing of the question as not a comparison, but as an independent drug strategy. I think it is a feasible drug strategy […] it is another option that is fairly impressive.”
John Deekan, MD, president of Inova Schar Cancer Institute, medical director for the Inova Schar Head and Neck Cancer program, voted against the sBLA.
"I think in 2020, it is hard to argue for this disease that an overlapping survival curve is hard to argue, given the toxicity we saw. I'm hoping the company will have overall survival final results sooner than 2023, so the application can be based on that solid [evidence]," said Deekan. "There was no improvement in quality of life and toxicity."
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).4 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.