Trials Demonstrate Which Treatments Physicians Should Use in EGFR+ NSCLC

Edgardo S. Santos Castillero, MD

Edgardo S. Santos Castillero, MD, founding partner, Florida Precision Oncology Research & Consulting, clinical affiliate associate professor, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, reviewed the case of a 73-year-old Asian man who was diagnosed with stage IV EGFR-mutant non-small cell lung cancer and discussed the treatment options he would consider for this patient.

Targeted Oncology™: What treatment options would you consider in the front line for this patient?

Santos Castirello: I think that everyone would put this patient on osimertinib [Tagrisso, because of his] exon 19 deletion. I would do the same….The patient has a brain lesion, so the osimertinib would penetrate the [blood-brain barrier].

Which therapies do the National Comprehensive Cancer Network (NCCN) guidelines suggest in this setting?

The latest version [shows] several options.1 Osimertinib is [cons idered] category 1 and preferred. The others that are category 1 are erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif] and dacomitinib [Vizimpro]. The category 2A [treatment] is erlotinib/ ramucirumab [Cyramza], which…shows impressive progressionfree survival [PFS], at least at this moment. We need to wait for the overall survival [OS] data. Then erlotinib and bevacizumab [Avastin] is category 2B.

Most [participants] do not have a problem at all. Cost to patient and patient assistance are tied, 27% for each of them. I would say cost to the patient would be one barrier. Patient assistance is good to have. Most in this group would not have any problem.

How have data shown efficacy for different treatments in this patient population?

The FLAURA study [NCT02296125] was presented several years ago.² This was for treatment-naive patients, all of them with exon 19 or 21–sensitive mutation and [a] good [performance status of] 0 or 1. Patients with stable central nervous system metastases were also allowed in this study. The primary end point was PFS, and [the] secondary end point was overall response rate and OS. This was osimertinib versus erlotinib/gefitinib. The median PFS was striking, at 18.9 months with osimertinib versus 10.2 months for gefitinib/erlotinib [HR, 0.46; 95% CI, 0.37-0.57; P < .0001]. The following year at the 2019 European Society for Medical Oncology annual meeting, the final OS was presented by [Suresh S.] Ramalingam, MD, and the study was positive.³ The median OS was 38.6 months versus 31.8 for gefitinib/erlotinib [HR, 0.799; 95.05% CI, 0.641-0.997; P = .0462]. Because of these OS data, osimertinib became the preferred agent in this particular population.

[All of the subgroups] were in favor of osimertinib except for the Asian patient population [and those with] EGFR mutation L858R. There is a difference between exon 18 and L858R in terms of how [osimertinib] affects the overall response rate when we use TKIs [tyrosine kinase inhibitors]. They are not the same, and we’ve known that for years—since the beginning of TKI history when we made this observation. I think that these data will influence [the use of] frontline osimertinib.

How does erlotinib play a role in this patient population? What trials look at this drug?

We know that there is synergy between pathways when we [treat patients with] dual inhibition. [Results from the] NEJ026 [UMIN000017069 trial], which was positive for PFS [with erlotinib and bevacizumab], [were] presented at the 2020 American Society of Clinical Oncology Annual Meeting. [NEJ026] was negative for OS.4 We have the Artemis trial [NCT02759614], the RELAY trial [NCT02411448], the J025567 [JapicCTI-111390 trial], and the small, phase 2 randomized trial conducted by Thomas Eldridge Stinchcombe, MD, [looking at combinations of erlotinib]. All the studies were positive for PFS except for Stinchcombe’s, maybe because the number of patients was too small at 88. But while you have a significant number of patients and all of them were randomized [in the other trials], you see that the PFS was in favor of the dual inhibition versus a TKI alone. At this moment, the only trial still remaining to see what happened with the OS is the RELAY trial, [other data for] which [were] presented this year.

In the forest plot of all the studies, everything is in favor of the combination [treatment in terms of] PFS and OS except for the Stinchcombe trial. Most of the impact was on PFS. In terms of resistance mutation at progression, there is no real difference between dual inhibition or EGFR TKI monotherapy. Two studies looked into this: one was ARTEMIS and the other was the RELAY trial.

What was the efficacy result of RELAY?

For the RELAY trial, the difference here [is] that we are not using bevacizumab [as in the other trials mentioned], we are using ramucirumab.⁵ The difference is that this is a monoclonal antibody that basically blocks that receptor, and by blocking that receptor you are not going to allow any VEGA, VEGB, or VEGF to go into that receptor. There is a different mechanism of action between ramucirumab and bevacizumab.

[RELAY] was a randomization of ramucirumab plus erlotinib versus placebo plus erlotinib. It was a double-blind placebo-controlled trial, and the therapy continued until progression of disease.

The study was strikingly positive. This is the highest PFS that we have seen [in this setting]. We have PFS reported at 19.4 months with ramucirumab plus erlotinib versus 12.4 months [HR, 0.59; 95% CI, 0.46-0.76; P < .0001], which usually is routinely what we expect for erlotinib; I would saya bit lower, but this includes sensitive mutation. There was a 41% decrease in mortality by using ramucirumab and erlotinib. OS is [not mature yet]. The subgroups by EGFR mutation showed [that in patients with] the exon 19 and the exon 21, [the PFS is] almost the same. We have not seen this before with any other TKI.

In terms of the treatment-related adverse events, bleeding and hemorrhage was from epistaxis, [gastrointestinal hemorrhage, and pulmonary hemorrhage]. The grade 3 [events were]

low, 1%, and grade 4, less than 1%. The issue was the hypertension, which was 24% for grade 3.

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed November 8, 2020. https://bit.ly/2HC0s7G}

_{2. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137}

_{3. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as firstline treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl 5):V914-V915. doi:10.1093/annonc/mdz394}

_{4. Landre T, Des Guetz G, Chouahnia K, et al. Angiogenesis inhibitor plus erlotinib versus erlotinib alone as first-line for advanced non-small cell lung-cancer harboring EGFR mutation. J Clin Oncol. 2020;38(suppl 15):9569. doi:10.1200/JCO.2020.38.15_suppl.9569}

_{5. Nakagawa K, Garon EB, Seto T; RELAY Study Investigators. 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}