Future of Frontline EGFR+ NSCLC Features TKI, Chemo Combos and Improved Molecular Profiling


Synergizing EGFR TKIs with antiangiogenic agents and chemotherapy, as well as improving the use of molecular classification, are novel strategies aimed at taking the frontline setting for patients with EGFR-mutant non–small cell lung cancer to the next level.

Mary Jo J. Fidler, MD

Mary Jo J. Fidler, MD

Synergizing EGFR TKIs with antiangiogenic agents and chemotherapy, as well as improving the use of molecular classification, are novel strategies aimed at taking the frontline setting for patients with EGFR-mutant non–small cell lung cancer (NSCLC) to the next level, according to Mary Jo J. Fidler, MD.1

“Adding VEGF2 monoclonal antibody and systemic chemotherapy improved outcomes with first-generation TKIs in patients with EGFR-mutated lung cancer. Biomarkers are being identified to identify poor-prognosis patients and those likely to transform into small cell lung cancer,” said Fidler, who is the medical oncology section chief and an associate professor in the Department of Internal Medicine of the Division of Hematology, Oncology and Cell Therapy, at Rush Medical College, Rush University Medical Center. “Future directions will likely capitalize on co-targeting EGFR with other co-mutations in select populations.”

In a presentation during the 18th Annual Winter Lung Cancer Conference®, a program hosted by the Physicians Education Resource (PER)®, LCC, Fidler highlighted a number of tactics that have been investigated and are on the horizon to up the treatment game of EGFR-mutant NSCLC.

Adding Antiangiogenic Inhibition

The synergy between EGFR inhibitors and antiangiogenic agents have been documented in multiple clinical trials. For example, in the open-label, phase 3 Japanese NEJ026 study, patients with treatment-naïve, stage IIIB to IV EGFR-mutant NSCLC were randomized to receive the combination of erlotinib (Tarceva) plus bevacizumab (Avastin; n = 112) or erlotinib alone (n = 114).

Interim results showed that the median progression-free survival (PFS) with the combination was 16.9 months (95% CI, 14.2-21.0) compared with 13.3 months for erlotinib alone (95% CI, 11.1-15.3), leading to a 40% reduction in the risk of disease progression or death (HR, 0.605; 95% CI, 0.417-0.877; P = .016).2 The strategy was replicated in the United States in a phase 2 trial, but the results were negative.3

However, promising results were seen in the phase 3 RELAY study (NCT02411448), in which patients with stage IV EGFR-positive NSCLC who harbored exon 19 deletions or exon 21 L858R mutations were randomized to receive the addition of ramucirumab (Cyramza) or placebo to erlotinib. Patients with known brain metastases were excluded from enrollment.

Data showed that the median PFS with the addition of ramucirumab was 19.4 months (95% CI, 15.4-21.6) compared with 12.4 months (95% CI, 11.0-13.5) for erlotinib alone (HR, 0.59; 95% CI, 0.46-0.76; P <.0001).4

Additionally, “no unexpected safety signals [were observed with the] addition of ramucirumab to erlotinib,” Fidler added. “What we don’t know is how overall survival [OS] was impacted by the addition of ramucirumab. What we do know is that in patients who progressed after erlotinib with or without ramucirumab, they were able to find the expected frequency of T790M resistance mutations; so, in theory, those patients would be eligible to receive osimertinib [Tagrisso] upon progression.”

Based on the RELAY data, the FDA approved the combination of erlotinib and ramucirumab in May 2020 as a frontline treatment for patients with metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations.

In the previously-treated setting, the combination of osimertinib and bevacizumab had shown intriguing activity in a phase 2 Japanese trial of 87 patients with EGFR T790M–positive NSCLC, some of whom had brain metastases and had received a prior VEGF inhibitor.5 Although the overall response rate was higher with the combination (68%) versus osimertinib alone (54%), the PFS was not improved (adjusted HR, 1.44), nor was the OS (HR, 0.94).

“It is important to note that the group that performed particularly poorly had received prior angiogeneic VEGF therapy and were treated with osimertinib plus bevacizumab on this phase 2 trial,” Fidler said. “The authors also looked to see whether discontinuing bevacizumab due to toxicities affected their PFS, and they thought it did not.”

The same combination was recently tested in the frontline setting in a single-center, interventional, single-arm, phase 1/2 trial of 49 patients. Results showed that the 1-year PFS rate, which was the study’s primary end point, was 76%. Additionally, the median PFS was 19 months (95% CI, 15-24).6 Fidler noted that 31% of patients had brain metastases and 8 patients withdrew consent for reasons that were unrelated to toxicity. Moreover, an inferior PFS was seen in those with persistent detectable EGFR-mutant circulating tumor DNA at 6 weeks.

Potential With Combining Chemotherapy

Dose intensification with chemotherapy is another combinatorial strategy being explored with EGFR TKIs in the frontline treatment of patients with EGFR-positive NSCLC. For example, in a phase 2 trial, 195 patients from 35 centers in Asia, all of whom had chemotherapy-naïve disease, were randomized 2:1 to receive gefitinib (Iressa) plus pemetrexed (n = 126) versus gefitinib alone (n = 65); the median number of pemetrexed cycles received was 12.

Findings showed that the median PFS was 15.8 months (95% CI, 12.6-18.3) with gefitinib/pemetrexed and 10.9 months with pemetrexed alone (95% CI, 9.7-13.8), leading to a two-sided P value of .028.7

In a bit of a different strategy, another phase 2 trial looked at concurrent (n = 41) versus sequential alternating gefitinib (n = 39) with carboplatin and pemetrexed in the same type of patient population. Data showed that the median PFS was 18.3 months (95% CI, 9.7-21.9) versus 15.3 months (95% CI, 11.3-17.4) with the concurrent and sequential arms respectively, which was not statistically significant (HR, 0.80; P = 0.20).8 However, the median OS was 41.9 months (95% CI, 35.1–not reached) and 30.7 months (95% CI, 23.2-40.5), respectively (HR, 0.55; P = .042).

Stemming from these findings, came an open-label, randomized phase 3 trial of gefitinib alone (n = 176) or combined with chemotherapy (n = 174) in patients with EGFR-positive, stage IIIB NSCLC not amenable to radical therapy or stage IV NSCLC. Twenty percent of patients had an ECOG performance status of 2, and close to 20% had brain metastases,9 Fidler noted. In the gefitinib-alone arm, patients received treatment for a median of 260 days compared with 327 days with gefitinib in the combination arm. Dose interruptions and reductions with gefitinib were similar between the 2 arms.

The estimated median PFS favored the combination arm, at 16 months (95% CI, 13.5-18.5) compared with 8 months (95% CI, 7.0-9.0) for single-agent gefitinib (HR, 0.51; 95% CI, 0.39-0.66; P <.001). The median OS was not reached with gefitinib/chemotherapy versus 17 months (95% CI, 13.5-20.5) with gefitinib alone (HR, 0.45; 95% CI, 0.31-0.65; P <.001).

Fidler called the PFS and OS data in this trial “striking.”

“These benefits, however, do come at increased toxicity. The investigators noted clinically relevant toxicity of 51% in the gefitinib plus carboplatin/pemetrexed versus 25% in the gefitinib arm alone,” noted Fidler. “Forty-four percent of patients treated with gefitinib alone went on to receive subsequent chemotherapy; 32% [received] carboplatin/pemetrexed.”

Using Molecular Characteristics to Drive Treatment Decisions

Biomarkers of poor prognosis in patients with EGFR-positive NSCLC have been identified, including WNT/β-catenin, cell cycle alterations, and co-amplification of HER2 or MET. Moreover, RNA sequencing may identify fusions that can be mechanisms of resistance that can be missed by DNA next-generation sequencing, Fidler said.

TP53, RB1, and NKX2-1 are abnormalities that have been seen in both early and late stages of disease, and some mutations, such as PIK3CA, occur more frequently with metastatic progression.10 These types of aberrations are seen across the EGFR subtypes of exon 19 deletions, exon 20 alterations, and exon 21 mutations; TP53 and RB1 have specifically been reported as early genetic events that are linked with small cell lung cancer transformation.11 Furthermore, higher tumor mutational burden in EGFR-positive NSCLC was also found to correlate with inferior outcomes12, as well as high neutrophil to lymphocyte ratio.13

Current ongoing trials are examining several of the combination therapeutic strategies in the frontline setting of advanced EGFR-mutant NSCLC: osimertinib plus ramucirumab (phase 2; NCT03909334), osimertinib plus bevacizumab (phase 3; NCT04181060), osimertinib combined with carboplatin/pemetrexed (phase 3 FLAURA2; NCT04035486), osimertinib with carboplatin/pemetrexed in patients with co-mutations in EGFR and TP53 (phase 3; NCT04695925), and osimertinib with cisplatin/etoposide in patients who also have p53 or Rb mutations (phase 1; NCT03567642).

“Patient input on study design and outcomes is critical with strategies involving dose intensification in patients with EGFR-positive lung cancer,” Fidler concluded.


1. Fidler MJ. What should we add to EGFR TKIs in newly diagnosed patients? Presented at: 18th Annual Winter Lung Cancer Conference; February 5-7, 2021; Virtual.

2. 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(5):625-635. doi:10.1016/S1470-2045(19)30035-X

3. Stinchcombe TE, Jänne PA, Wang X, et al. Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(10):1448-1455. doi:10.1001/jamaoncol.2019.1847

4. Nakagawa K, Garon EG, 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. doi:10.1016/S1470-2045(19)30634-5

5. Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M–mutated non–small cell lung cancer previously treated with epidermal growth factor receptor–tyrosine kinase inhibitor. JAMA Oncol. Published online January 7, 2021. doi:10.1001/jamaoncol.2020.6758

6. Yu HA, Schoenfeld AJ, Makhnin A, et al. Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers. JAMA Oncol. 2020;6(7):1048-1054. doi:10.1001/jamaoncol.2020.1260

7. Cheng Y, Murakami H, Yang P-C, et al. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016;34(27):3258-3266. doi:10.1200/JCO.2016.66.9218

8. Sugawara S, Oizumi S, Minato K, et al. Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol. 2015;26(5):888-894. doi:10.1093/annoc/mdv063

9. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154

10. Skoulides F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495-509. doi:10.1038/s41568-019-0179-8.

11. Lee J-K, Lee J, Kim S, et al. Clonalhistory and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.J Clin Oncol. 2017;35(26):3065-3074. doi:10.1200/JCO.2016.71.9096

12. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11). doi:10.1158/1078-0432

13. Rouhani S.The neutrophil-to-lymphocyte ratio is a prognostic biomarker in patients with EGFR mutated advanced NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract P76.30.

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