Ramucirumab Plus Erlotinib Shows PFS Benefit in Frontline EGFR+ NSCLC

Kazuhiko Nakagawa, MD

Kazuhiko Nakagawa, MD

Patients with treatment-naïveEGFR-mutant non—small cell lung cancer (NSCLC) experienced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with the combination of ramucirumab (Cyramza) and erlotinib (Tarceva) compared with erlotinib alone, according to the results of the phase III RELAY trial which was recently published inThe Lancet Oncology.^1,2

Data specifically showed that the combination was associated with a median PFS of 19.4 months compared with 12.4 months with erlotinib and placebo, leading to a 41% reduction in the risk of disease progression or death (HR, 0.59; 95% CI, 0.46-0.79;P≤.0001) at a median follow-up of 20.7 months.

There were no new safety signals and the tolerability observed in the trial was consistent with what has been previously observed with data for ramucirumab and erlotinib as single agents. Moreover, these study results are the basis for global regulatory submissions, which have been made in the United States and European Union, stated Lilly Oncology, the developer of ramucirumab, in a press release. A submission in Japan is planned by the end of 2019.

"The findings from RELAY show the utility of targeting the VEGFR and EGFR pathways together in this setting, and validate previous non-clinical and clinical studies which demonstrated interactions between EGFR and VEGFR2 signaling in the setting ofEGFRmutations," lead study investigator Kazuhiko Nakagawa, MD, Department of Medical Oncology, Kindai University Faculty of Medicine, stated in a press release.

InEGFR-mutant NSCLC, most patients receive several lines of therapy, Lilly stated in the press release. EGFR TKIs, one of which is erlotinib, a first-generation EGFR TKI, are standard options for this patient population.

"Although EGFR TKIs have proven effective for the first-line treatment ofEGFR-mutated non—small cell lung cancer, most patients will experience disease progression and prognosis remains poor,” Nakagawa stated in the press release. “These results suggest the combination of Cyramza plus erlotinib has the potential to be an important first-line treatment option for people with metastaticEGFR-mutated non—small cell lung cancer."

The multicenter, double-blind, phase III RELAY trial accrued 449 patients with stage IV NSCLC harboring anEGFRexon 19 deletion or exon 21 L858R mutation, who had an ECOG performance status of 0 to 1. Patients were excluded if they had a known EGFRT790M mutation, prior EGFR TKI or chemotherapy treatment, or brain metastases.

Patient characteristics were well balanced between the study arms. The median patient age was 65 years and 63% of patients were female. Three-fourths of patients were Asian and one-quarter of patients were white. About 60% of patients in each arm were never-smokers and half the patients in each arm had an ECOG performance status of 0.

Patients were randomized to erlotinib at 150 mg/day plus either placebo (n = 225) or ramucirumab (n = 224) at 10 mg/kg every 2 weeks. Treatment was administered until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints included safety, overall survival (OS), overall response rate (ORR), and duration of response.

Results of the study were previously presented at the 2019 ASCO Annual Meeting.³The PFS benefit with the ramucirumab combination in the RELAY trial was observed across several key subgroups, including EGFRmutation type. Among patients with exon 19 deletions, the median PFS was 19.6 months with the combination versus 12.5 months with erlotinib alone (HR, 0.651; 95% CI, 0.469-0.903). Among those with exon 21 L858R mutations, the median PFS was 19.4 months versus 11.2 months, respectively (HR, 0.618, 95% CI, 0.437-0.874).

OS data remain immature and the median interim OS has not been reached in either arm. At the data cutoff, there were 37 OS events in the combination arm and 42 in the control arm, with an HR of 0.832 (95% CI, 0.532-1.303) favoring the ramucirumab group. The 1- and 2-year OS rates are 93% versus 94% and 83% versus 79%, with the combination and erlotinib alone, respectively.

Likewise, the data are immature for PFS2. There were 61 and 79 PFS2 events in the combination and control arms, respectively, with an HR of 0.690 (95% CI, 0.490-0.972) favoring the ramucirumab arm.

The ORRs were 76% with the combination and 75% in the control arm. The disease control rate was 95% versus 96%, respectively. The median duration of response favored the ramucirumab arm at 18 months compared with 11.1 months for the erlotinib-alone group.

Seventy-one percent of patients in the ramucirumab arm and 81% of patients in the erlotinib-alone arm had discontinued treatment at the data cutoff date of January 23, 2019. Progressive disease was the primary reason for discontinuation in both arms.

Regarding safety, the rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 72% with the ramucirumab combination compared with 54% with erlotinib alone. The rates of serious TEAEs were 29% versus 21%, respectively. The rates of TEAE-related treatment discontinuation, dose adjustment, and death in the combination versus control arms were 13% versus 11%, 85% versus 71%, and 1% versus 0%, respectively.

Two patients in the ramucirumab arm and 3 patients in the control arm had grade 4 increased alanine aminotransferase level. One patient receiving erlotinib alone had grade 4 increased aspartate aminotransferase (AST) level. The most common grade 3 TEAEs in the ramucirumab arm were hypertension (24% vs 5% with erlotinib alone), acneiform dermatitis (15% vs 9%, respectively), increased ALT (8% vs 6%), diarrhea (7% vs 1%), and increased AST (5% vs 4%).

"The RELAY data are the strongest clinical evidence to date for targeting both the EGFR and VEGFR pathways to treat this type of cancer. We're excited by these results and the promise they may hold for metastatic non-small cell lung cancer patients with anEGFRmutation," Maura Dickler, MD, vice president of late phase development, Lilly Oncology, stated in the press release. "The RELAY trial is another example of Lilly's deep commitment to providing new treatment options to people with lung cancer, and the value that Cyramza can provide in advanced or metastatic cancers."

References

1. Lilly's CYRAMZA® (ramucirumab) Phase 3 Data in First-Line EGFR-Mutated Non-Small Cell Lung Cancer Published in The Lancet Oncology. Lilly Oncology. Published October 7, 2019. https://bit.ly/2p2Az7m. Accessed October 7, 2019.
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 [published online ahead of print October 4, 2019]. Lancet Oncol. 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; abstr 9000). doi: 10.1200/JCO.2019.37.15_suppl.9000.