Immunotherapy May Have Place Among TKI Boom in EGFR+ NSCLC

Within the last decade, 4 tyrosine kinase inhibitors have been approved for the frontline treatment of patients with EGFR-positive non–small cell lung cancer.

Christine Bestvina, MD

Within the last decade, 4 tyrosine kinase inhibitors (TKIs) have been approved for the frontline treatment of patients with EGFR-positive non—small cell lung cancer (NSCLC). However, in recent years, both investigators and patients have been curious about the potential for immunotherapy. This should not underscore the successes of agents such as osimertinib (Tagrisso), though, said Christine Bestvina, MD.

"Significant progress has been made in the field of EGFR-mutant lung cancer since the initial approval of erlotinib (Tarceva) in 2004," said Bestvina. "Even in just the past 4 years, we have gone from having 3 frontline TKIs approved, to the approval of osimertinib.”

In a presentation during the 2018 OncLive® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Bestvina, an assistant professor of medicine, Department of Medicine, Hematology/Oncology, University of Chicago Medicine, discussed updates in EGFR-positive NSCLC.

According to the NCCN guidelines, there are 4 TKIs recommended for frontline use in patients with EGFR-positive NSCLC. These agents are erlotinib, afatinib (Gilotrif), gefitinib (Iressa), and osimertinib.

Erlotinib has traditionally been the favored frontline approach for patients in the United States since its approval almost 10 years ago, Bestvina explained. A demonstration of improvement in progression-free survival (PFS) was seen when compared with chemotherapy in patients with an EGFR mutation. The common adverse events (AEs) that are seen with erlotinib include rash, fatigue, diarrhea, and lack of appetite.

Globally, gefitinib had been the primary favored TKI for patients with EGFR mutations, Bestvina said. This agent also showed an improvement in PFS when combined with chemotherapy. The safety profile is similar to that of erlotinib, which is rash, diarrhea, and lack of appetite. Additionally, patients treated with gefitinib can also experience stomatitis and neurotoxic effects. This agent was approved by the FDA in 2015, based on findings from the single-arm, phase IV IFUM trial in which gefitinib had an overall response rate (ORR) of 50% (95% CI, 0.41-0.59) in 106 treatment-naïve patients with EGFR-positive NSCLC.1

The third frontline TKI approved was afatinib. Bestvina noted that toxicities with afatinib are significant, with high proportions of patients experiencing some grade of diarrhea, rash, stomatitis, and anorexia. Afatinib was originally approved by the FDA in 2013 for the treatment of patients with metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions. This indication was expanded in 2016 to include patients with squamous histology following progression on a platinum-based chemotherapy.

The FDA expanded the indication of afatinib once more in January 2018 to include the frontline treatment of patients with metastatic NSCLC whose tumors harbor uncommon EGFR alterations in L861Q, G719X, and/or S768I. This most recent expansion was based on findings from 32 patients in the phase II LUX-Lung 2 trial and the randomized phase III trials known as LUX-Lung 3 and LUX-Lung 6. The confirmed ORR with afatinib in these patients was 66% (95% CI, 47%-81%).2

Osimertinib most recently entered the treatment landscape for these patients. This TKI was first studied in patients with a T790M mutation, which is the resistance mutation to most common frontline TKI therapies, Bestvina explained. Additionally, the AE profile of osimertinib was improved when compared with prior TKIs, with a lower degree of rash, diarrhea, and anorexia, as well as significantly less grade ≥3 toxicities.

"The other benefit of osimertinib is the excellent CNS activity," noted Bestvina. "Patients do demonstrate a response in CNS metastases to osimertinib. [The] CNS PFS showed a significant improvement when compared with platinum-based chemotherapy."

These positive results in the second-line setting led investigators to believe that it might be beneficial in the first-line setting, which led to the initiation of the FLAURA study. Phase III findings of this trial led to the FDA approval of osimertinib as a first-line therapy for patients with NSCLC whose tumors harbor EGFR mutations, including exon 19 deletions or exon 21 L858R substitution mutations in April 2018.3

The superior safety profile to erlotinib was echoed in the frontline FLAURA results of osimertinib. In stage IV disease, this aspect plays a very significant role in the treatment of these patients, Bestvina emphasized, as care is mostly viewed as palliative and not curative.

Although there has been a boom of immunotherapy trials in lung cancer over the last few years, patients with targetable mutations are often excluded.

"In my clinical experience, patients with EGFR mutations feel left out; they feel like they have been forgotten in this immunotherapy 'gold rush,'" said Bestvina.

One trial that did include a cohort of patients with EGFR mutations was the ATLANTIC trial of durvalumab (Imfinzi) in the third-line setting. Even in the PD-L1 expression group, the response was still limited to 12.2% with a PFS of 1.9 months.4

Bestvina noted the phase II study of pembrolizumab (Keytruda) in EGFR-mutant, PD-L1—positive, TKI-naïve patients with advanced NSCLC as a cautionary tale of single-agent immunotherapy in this population. The trial closed after the enrollment of 11 patients showed a response rate of 0.

In the PACIFIC study however, there was a trend toward benefit for PFS for patients with EGFR-positive NSCLC. The overall survival (OS) benefit for this patient group is not known, though.

The IMpower150 study looked at carboplatin plus paclitaxel and bevacizumab (Avastin) with or without atezolizumab (Tecentriq). In the EGFR/ALK-positive cohort, there was a trend toward benefit in the atezolizumab arm. Patients with EGFR and ALK alterations in the intent-to-treat group showed a median OS with the addition of atezolizumab of 19.8 months compared with 14.9 months without the PD-L1 inhibitor (HR, 0.76; 95% Cl, 0.63-0.93).5,6

"If you want to use immunotherapy for your patients, it may be best to combine it with chemotherapy," concluded Bestvina. "The role of immunotherapy for EGFR-positive patients continues to be clarified."


  1. FDA. Erlotinib (Tarceva). Published October 18, 2016. Accessed November 1, 2018.
  2. Yang JC-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harboring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi: 10.1016/ S1470-2045(15)00026-1.
  3. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
  4. Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet. 2018;19(4):521-536. doi: 10.1016/S1470-2045(18)30144-X.
  5. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36 (suppl; abstr 9002).
  6. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.