Erlotinib Plus Ramucirumab: Ready for Prime Time?

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The treatment of epidermal growth factor receptor (EGFR)-positive lung cancer changed dramatically after the results of the FLAURA trial showed improved progression-free survival with the third-generation EGFR tyrosine kinase inhibitor osimertinib as first-line therapy compared with earlier-generation tyrosine kinase inhibitors (erlotinib and gefitinib). Further follow-up confirmed longer overall survival for patients in the osimertinib arm (38.6 vs 31.8 months).

Narjust Duma, MD

Narjust Duma, MD

Gilberto Lopes, MD, MBA, FAMS, FASCO

Gilberto Lopes, MD, MBA, FAMS, FASCO

In the United States, the U.S. Food and Drug Administration granted osimertinib first-line approval in April 2018. However, osimertinib is not available in many parts of the world. In 2019, the National Institute for Health and Care Excellence in the United Kingdom did not grant osimertinib approval in the first-line setting; the committee decided the drug did not offer enough extra benefit for the offered cost to patients compared with existing treatments. Osimertinib is also not available in many countries in Latin America and Africa, where erlotinib or gefitinib are frequently used as the first-line therapy option for EGFR-mutated non–small cell lung cancer (NSCLC), when available.

Despite these changes in practice, metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution remains a lethal disease, with new data showing limited responses to immune checkpoint inhibitors after disease progression on tyrosine kinase inhibitors. Therefore, there is a critical need to develop new tyrosine kinase inhibitor–based therapies. As reviewed in this issue of The ASCO Post, the global phase III RELAY trial aimed to study the combination of erlotinib plus ramucirumab vs erlotinib monotherapy in patients with newly diagnosed EGFR-mutated NSCLC.

RELAY Trial Background

Erlotinib was the first tyrosine kinase inhibitor to receive approval for the treatment of EGFR-positive NSCLC and continues to be the most widely available agent. Preclinical data suggested that the combination of vascular endothelial growth factor (VEGFR) inhibitors with EGFR tyrosine kinase inhibitors could result in longer duration of responses.1

Early trials combining erlotinib with the VEGFR inhibitor bevacizumab failed to reveal significant improvements in overall survival but showed evidence of increased efficacy. The JO25567 phase II trial evaluated erlotinib plus bevacizumab in a cohort of Japanese patients and revealed improved progression-free survival in the combination arm (16.0 vs 9.7 months in the erlotinib arm), with these data providing the basis for approval of the combination in the European Union and Japan.2 The median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. The JO25567 investigators aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with nonsquamous NSCLC with activating EGFR mutation–positive disease.

In the open-label, randomized, multicenter JO25567 study, patients from 30 centers across Japan with stage IIIB/IV or recurrent nonsquamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib at 150 mg/d plus bevacizumab at 15 mg/kg every 3 weeks or erlotinib at 150 mg/d monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomization was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumor assessment at least once after randomization.

Between February 21, 2011, and March 5, 2012, 154 patients were enrolled. A total of 77 were randomly assigned to receive erlotinib and bevacizumab and 77, erlotinib alone, of whom 75 patients in the erlotinib-plus-bevacizumab group and 77 in the erlotinib-alone group were included in the efficacy analyses. Median progression-free survival was 16.0 months (95% confidence interval = 13.9–18.1 months). However, these studies included Japanese patients alone, and it was unknown whether the combination would show the same efficacy in other patient populations. This question was one of the starting points for the RELAY trial.3,4

Key Findings

As reported by Nakagawa and colleagues,4 the RELAY trial showed that the combination of erlotinib and ramucirumab significantly improved progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated NSCLC (19.4 vs 12.4 months). Overall survival data are still immature, and median overall survival was not reached for either group at the time of data cutoff.

Grade 3 or 4 adverse events were more common in the combination arm (72% vs 54%), with the most common toxicities in those patients including hypertension (24%) and dermatitis acneiform (15%). Serious adverse events were also more common in the combination arm (29% vs 21%). No new toxic events were identified as a result of the combination, but ramucirumab appeared to increase the incidence and severity of several erlotinib-associated adverse events, such as dermatitis acneiform and diarrhea.

One important factor reported in the study is that patients did not develop higher rates of resistance with the combination. A similar percentage of patients in the two arms developed T790M mutations (25% vs 30%), suggesting that patients could still receive osimertinib after disease progression.

The combination of erlotinib and ramucirumab may potentially give patients the opportunity to get a regimen that might provide similar survival benefits to osimertinib if that agent is not available in their country—but we should ask ourselves how widely accessible ramucirumab is in those countries. Also, is the reported survival benefit enough for the combination to be approved by local health authorities? Why would they approve this combination instead of single-agent osimertinib? In the end, the combination regimen may be more expensive due to the need for an intravenous infusion every 2 weeks, more frequent doctor visits, laboratory work, and higher rates of adverse events than an oral regimen like osimertinib.

Other Considerations

As the science and treatment of lung cancer continue to advance rapidly—like never before—ongoing clinical trials need to evolve, as well. Although we use the RELAY study as an example, many trials can evolve during their course as new agents are being approved for lung cancer by, for example, incorporating new treatment arms or combinations. However, it must be taken into account that this approach may bring growing expenses and changes in the sample size and homogeneity of the sample.

As noted, one of the RELAY study goals was to validate the combination in a Western subgroup of patients with EGFR-mutated-NSCLC, but non-Hispanic whites represented only 23% and 21% of the study patients in the combination arm and placebo-plus-erlotinib arm, respectively. A significant lack of representation of other racial and ethnic groups (eg, Hispanics and blacks) also limits the generalization of the data.

In summary, the results of the RELAY study showed promising results for the combination of erlotinib and ramucirumab in the first-line setting for EGFR-mutated NSCLC compared with erlotinib monotherapy. No new toxicities were identified, but higher rates of adverse events were observed in the combination arm. Overall survival results are immature, and the data should be considered with caution, as other agents like osimertinib are already approved in this setting and may provide similar outcomes with a potentially better toxicity profile. Nevertheless, we optimistically await overall survival results, and we hope that new therapeutic approaches continue to appear in the EGFR-mutated NSCLC arena. 

Dr. Duma is a member of the hematology/oncology faculty, Carbone Cancer Center at the School of Medicine and Public Health at University of Wisconsin–Madison. Dr. Lopes is Medical Director for International Programs, Associate Director for Global Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami. 

DISCLOSURE: Dr. Duma has had a consulting/advisory role with Inivata. Dr. Lopes has received honoraria from Boehringer Ingelheim; has had a consulting/advisory role with AstraZeneca and Pfizer; has received research funding from Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, Adaptimmune, BMS, and GSK; and has received travel/accommodation expenses from Boehringer Ingelheim, Pfizer, E.R. Squibb & Sons, and Janssen.


1. Wang Z, Wu F, Yan B, et al: Application of anti-angiogenic therapy in non-small cell lung cancer. Chinese J Clin Oncol 45:973-979, 2018.

2. Seto T, Kato T, Nishio M, et al: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567). Lancet Oncol 15:1236-1244, 2014.

3. Garon EB, Reck M, Paz-Ares L, et al: Treatment rationale and study design for the RELAY study. Clin Lung Cancer 18:96-99, 2017.

4. Nakagawa K, Garon EB, Seto T, et al: Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY). Lancet Oncol. October 4, 2019 (early release online).

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