Kazuhiko Nakagawa, MD, PhD, is a professor in the Department of Medical Oncology, Kindai University, Faculty of Medicine, in Japan, and he served as the lead principal investigator on the RELAY study, which investigated ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced NSCLC.1 In the following interview, Dr. Nakagawa discusses the trial’s results, as well as the implications of these results for clinical practice.
Q: What was the rationale for the combination of erlotinib and ramucirumab in the RELAY study?
A: The rationale for the erlotinib/ramucirumab combination therapy was supported by preclinical and clinical data suggesting that the VEGF and EGFR pathways are interconnected. It is well understood that EGFR-mutant tumors are more “VEGF dependent” than EGFR wild-type tumors, and that dual blockade of the EGFR and VEGF pathways would be more effective than either approach alone. Therefore, dual EGFR/VEGF pathway inhibition presents a viable strategy to achieve improved efficacy outcomes in EGFR-mutated NSCLC.
Preclinical data suggest the dual blockade of VEGF and EGFR pathways are more effective than either approach alone. Erlotinib inhibits the oncogenic driver, while ramucirumab inhibits targets downstream of the oncogenic driver. The VEGF signaling pathway is continuously upregulated in EGFR-mutated NSCLC cells.2 EGFR TKIs down-regulate the VEGF signaling pathway; however, VEGF signaling upregulates during EGFR TKI monotherapy.3,4 Duration of antitumor activity with EGFR TKIs and anti-angiogenic therapy is longer than EGFR TKI monotherapy because the combination of EGFR TKIs and anti-angiogenic therapy suppresses upregulation of VEGF signaling.5,6 The RELAY data showed superior PFS for the ramucirumab/erlotinb combination (mPFS 19.4 vs. 12.4 months; HR 0.591, 95% CI [0.46, 0.76]); p < 0.0001).
This strategy has been confirmed in clinical trials, reporting improved efficacy for the anti-angiogenic agent bevacizumab in combination with the EGFR TKI erlotinib in patients with EGFR-mutated NSCLC as initially shown in subgroup analyses of patients with EGFR–mutation positive disease enrolled in the BeTa and ATLAS studies and subsequently prospectively evaluated in the JO25567 study, which included patients with EGFR-mutated disease only. The RELAY study targeted the VEGFR and EGFR pathways together (with ramucirumab/erlotinib) in this setting and validates previous nonclinical and clinical studies that demonstrated interactions between EGFR and VEGFR2 signaling in the setting of EGFR mutations.
It is important to note that, at the time of RELAY study initiation in 2015, erlotinib was a standard of care in first-line EGFR mutation-positive NSCLC. At that time, three EGFR TKIs (erlotinib, gefitinib, and afatinib) were approved for use as first-line treatment of NSCLC with activating EGFR mutations; however, only erlotinib was globally approved at the time the RELAY study was initiated. Erlotinib remains a recommended treatment option for this indication according to National Comprehensive Cancer Network, European Society for Medical Oncology, and the Japan Lung Cancer Society guidelines. No head-to-head studies had been performed, which would indicate whether one of those EGFR TKIs had superior efficacy to another, and the safety profiles were similar. I would like to note that when we started RELAY, osimertinib was not available yet and was approved for T790M-positive resistance and/or 1L settings during the course of the study.
Q: Do you think that we would have seen a similar PFS benefit if bevacizumab had been used in lieu of ramucirumab?
A: This question can only be rightfully answered in a prospective randomized clinical trial. Ramucirumab and bevacizumab are both VEGF antagonists; however, ramucirumab specifically binds to the VEGF receptor 2, which blocks the binding of the three ligands: VEGF-A, VEGF-C, and VEGF-D. This is unique from other molecules that specifically inhibit the VEGF-A ligand, such as bevacizumab. Clinical studies suggested improved efficacy for the combination of erlotinib/bevacizumab in patients with NSCLC with activating EGFR mutations.
In the Japanese JO25567 and NEJ026 randomized phase II and III, open-label studies of bevacizumab/erlotinib versus erlotinib alone as first-line treatment in patients with EGFR-mutated NSCLC, the median PFS was 16.0 months (95% CI [13.9, 18.1]) with erlotinib/bevacizumab and 9.7 months (CI [5.7, 11.1]) with erlotinib alone (HR 0.54, 95% CI [0.36, 0.79]; log-rank test p = 0.0015)7 and 16.9 months (95% CI [14.2, 21.0]) in the bevacizumab/erlotinib group compared with 13.3 months (CI [11.1, 15.3]) for patients in the erlotinib-alone group (HR 0.605, 95% CI [0.417, 0.877]; p = 0.016).7,8
RELAY was a global, randomized, double-blind, placebo-controlled phase III study in patients with previously untreated EGFR-mutated metastatic NSCLC. RELAY demonstrated superior PFS for ramucirumab/erlotinib (19.4 months [95% CI [15.4, 21.6]) compared to placebo/erlotinib (12.4 months [11.0, 13.5]; HR 0.59 (95% CI [0.46, 0.76]; p < 0.0001).1
Q: Does the PFS benefit seen in RELAY open the door to sequencing with osimertinib to follow this combination at the time of progression if a patient’s tumor develops the T790M resistance mutation?
A: Treatment of EGFR-mutant NSCLC remains a major challenge. There has been clear progress, but resistance to EGFR inhibitors inevitably develops, leaving patients with few options beyond chemotherapy-based regimens. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is the T790M point mutation. This mutation is detected in 30% to 60% of patients after treatment with first- or second-generation EGFR TKIs.9,10 The third-generation EGFR TKI osimertinib was specifically developed to overcome T790M resistance to first- and second-generation TKIs, while also inhibiting the activating EGFR mutations. Although improved efficacy outcomes have been achieved with use of osimertinib as first-line therapy, the heterogeneous and mostly non-targetable mechanisms of resistance to osimertinib prevent subsequent therapy with EGFR TKIs. The remaining treatment options are chemotherapy-based regimens, which are relatively ineffective in EGFR-mutated disease and are associated with a wide range of toxicities.
One of the treatment goals is to delay disease progression and use of chemotherapy for as long as possible while maintaining a good quality of life. Physicians must consider all available options when discussing a treatment strategy with their patients. For example, using a first- or second-generation treatment could offer a median PFS of 9 to 15 months; however, approximately 50% of patients will develop a T790M mutation. These patients can prolong time on targeted therapy by receiving osimertinib, which specifically targets a T790M population, and thereby prolong time on targeted therapy by months before transitioning to chemotherapy. Patients with T790M-negative disease will immediately proceed to chemotherapy.
In RELAY, patients for whom EGFR activating mutations were detectable in the post-progression liquid biopsy sample, the rates of post-progression EGFR T790M mutations were similar between treatment arms at 43% in the ramucirumab plus erlotinib arm and 47% in the placebo plus erlotinib arm. So, the addition of ramucirumab to erlotinib does not appear to alter the proportion of patients with a T790M mutation at the time of progression on first-generation TKIs.
The RELAY dual-targeted strategy, therefore, provides us with an option to start with a highly effective targeted regimen and for the approximately 50% of patients who develop T790M resistance, osimertinib would remain a treatment option. This approach would maximize the time on EGFR-targeted therapies and potentially delay the time to platinum-doublet chemotherapy.
In fact, in the RELAY trial, 74% of patients went on to EGFR TKIs, and only 23% of patients went on to chemotherapy as the first subsequent therapy. By contrast, there are currently no targeted agents approved for patients whose disease progresses on osimertinib; therefore, it is unsurprising that in the FLAURA study, 68% of patients whose disease progressed went on to chemotherapy as their first subsequent therapy.
Having said that, it is important to mention that RELAY was not a “sequencing study.” There remains a need to determine the appropriate sequencing of EGFR TKIs in this setting, and prospective studies will be needed to confirm whether the treatment sequencing is improving overall treatment outcomes.
Q: What is the current standard approach to EGFR-mutated NSCLC in Japan?
A: The number of deaths from lung cancer in Japan was approximately 74,000 in 2017—the highest among all cancer types. It has also been reported that a high percentage of NSCLC with EGFR mutations occur in Asia, including Japan (Asia vs. North America and South America vs. Europe: 38.4% vs. 24.4% vs. 14.1%).
In Japan, the first-generation EGFR TKIs gefitinib and erlotinib, second-generation EGFR TKIs afatinib and dacomitinib, and the third-generation EGFR TKI osimertinib are approved. Approximately 80% of EGFR-mutated NSCLC receive first line therapy with osimertinib in Japan at the moment.
In addition to these EGFR TKI monotherapies, phase II and phase III trials comparing bevacizumab/erlotinib combination therapy to erlotinib monotherapy were conducted in Japan, and the combination therapy of bevacizumab/erlotinib prolonged PFS statistically significantly in both studies.7,8 However, the use of this combination therapy is limited in the real clinical practice in Japan because it is not officially approved from the Japanese regulatory agency.
In addition, phase III trials comparing combination therapy of gefitinib plus chemotherapy to gefitinib monotherapy were conducted in Japan, and the combination therapy of gefitinib plus chemotherapy showed a statistically significant increase in PFS compared to gefitinib monotherapy and was tolerable.11
The RELAY regimen is not approved in Japan at this time; however, once it is approved, erlotinib/ramucirumab combination therapy will be a treatment option for first-line NSCLC with EGFR mutations.
Q: Do you have an explanation for why the combination of erlotinib plus ramucirumab affected exon 21 EGFR (L858R) more than exon 19 EGFR? Was there no difference between EGFR exon 19 and the intent-to-treat population in terms of PFS?
A: Among the various types of EGFR-activating mutations, exon 19 deletion and exon 21 L858R mutations constitute approximately 90% of all EGFR mutations and are sensitive to first-, second-, and third-generation TKIs. Presence of an EGFR mutation predicts sensitivity to EGFR TKIs, although the treatment benefit may differ depending on the EGFR mutation type. Historically, exon 21 mutations do worse on single-agent EGFR-TKIs compared to exon 19 mutations, irrespective of the EGFR-TKI generation used.12
Although these two common mutations are regarded as similar in predicting the benefit of EGFR TKIs, subgroup analyses of landmark studies and meta-analyses suggest that the benefit of EGFR TKIs is less in patients with exon 21 L858R than in exon 19 deletions. This difference was observed regardless of the generation of EGFR TKI used.
If we look at the totality of the RELAY PFS data, the mPFS delta in PFS versus control and 1-year PFS data for exon 21 mutations are as good as for exon 19 mutations, with PFS HRs that are also consistent.
In RELAY, patients treated with ramucirumab plus erlotinib with an exon 21 L858R mutation had similar treatment benefit as patients with an exon 19 deletion (exon 21 L858R mutation median PFS: 19.4 [14.1, 21.9]) vs. 11.2 [9.6, 13.8] HR: 0.618 [0.437, 0.874] and exon 19 deletion median PFS: 19.6 [15.1, 22.2] vs. 12.5 [11.1, 15.3] HR: 0.651 [0.469, 0.903] ramucirumab plus erlotinib versus placebo plus erlotinib, respectively).
The magnitude of PFS benefit observed for exon 21 L858R was equivalent to that of exon 19 deletion, and to our knowledge, the median PFS for exon 21 L858R is the longest reported to date for a targeted treatment approach, albeit in a population without central nervous system metastasis.
Q: From your perspective, is an EGFR sequencing approach still a viable option nowadays?
A: Yes, it is all about the overall treatment plan and how to maximize the treatment opportunities. With different first-line treatment options with similar PFS outcomes, sequencing is, in my opinion, a valid option to further improve treatment outcomes. Depending on the emerging resistance pattern, it may prolong the time patients can be treated with EGFR TKIs, thereby delaying the time to chemotherapy. All patients with metastatic EGFR-mutated NSCLC will eventually have disease progression on first-line EGFR TKI treatment and should receive a second-line treatment guided by T790M testing. Osimertinib, a third-generation TKI, was specifically developed to overcome this resistance and was initially approved as the second-line therapy for patients who develop T790M mutations on first-line therapy.
RELAY was a robust and well-conducted double-blind global study, where ramucirumab/erlotinib provided superior PFS compared to placebo plus erlotinib in first-line metastatic EGFR-mutated NSCLC. In addition, ramucirumab does not alter the proportion of patients with T790M mutations at the time of progression, so further treatment with the targeted agent osimertinib is possible in those patients. This leaves patients and treating physicians with more treatment options. Expanding the selection of effective first-line options provides oncologists and patients more choices and may delay the time to chemotherapy-based regimens.
1. 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.
2. Hung MS, Chen IC, Lin PY, et al. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer. Oncol Lett. 2016;12(6):4598-4604.
3. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res. 2006;66(6):3197-3204.
4. Masuda C, Yanagisawa M, Yorozu K, et al. Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model. Int J Oncol. 2017;51(2):425-434.
5. Naumov GN, Nilsson MB, Cascone T, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15(10):3484-3494.
6. Kayatani H, Ohashi K, Imao T, et al. Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer. Cancer Res. 2016; 76(14 suppl.). Abstract 5198.
7. 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): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244.
8. 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. Lancet Oncol. 2019;20:625-635.
9. Seto T, Nogami N, Yamamoto N, et al. Real-World EGFR T790M Testing in Advanced Non-Small-Cell Lung Cancer: A Prospective Observational Study in Japan. Oncol Ther. 2018;6:203-215.
10. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017;35(12):1288-1296.
11. Hosomi Y, Morita S, Sugawara S, et al. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non–Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 2020;38(2):115-123.
12. Sheng M, Wang F, Zhao Y, et al. Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis. Eur J Clin Pharmacol. 2016;72(1):1-11.