EGFR-Targeted Activity Helps Differentiation Between TKIs in NSCLC

Gregory J. Riely, MD, PhD

The treatment paradigm for EGFR-mutant non—small cell lung cancer (NSCLC) has grown significantly with many EGFR TKIs now available to treat patients with this disease. To differentiate between these TKIs though, oncologists can look to the spectrum of EGFR mutations each agent is targeted to hit, both the common and the uncommon ones.

In a presentation during the 16th Annual Winter Lung Conference^™, Gregory J. Riely, MD, PhD, discussed the spectrum of activity of many of these FDA-approved EGFR TKIs.

Riely, vice chair of clinical research in the Department of Medicine at Memorial Sloan Kettering Cancer Center, explained that all of the EGFR TKIs, first through third generation, are active against the common mutations, EGFR L858R and exon 19 deletion mutations. Additionally, both the first- and second-generation agents are all active against EGFR wild-type, which leads to the common adverse events (AEs) of rash and diarrhea. However, not all are active against T790M mutations, HER2 amplification, and beyond.

Afatinib (Gilotrif) demonstrated significant activity in a number of less common EGFR mutations in an analysis from the LUX-Lung trials, including point mutations in exons 18 through 21 with a confirmed objective response rate of 66% (95% CI, 47%-81%).¹ Based on these data, afatinib gained an expanded approval in January 2018 for the treatment of patients whose tumors harbor EGFR L861Q, G719X, and/or S768I alterations.

Unlike other FDA-approved options, the second-generation agents afatinib and dacomitinib (Vizimpro) both demonstrate activity against HER2, which Riely mentioned could be beneficial, as suggested by data from the ARCHER 1050 trial.

ARCHER 1050 was a randomized phase III trial that compared dacomitinib with the first-generation EGFR TKI gefitinib (Iressa) for the treatment of newly diagnosed patients with EGFR-mutant advanced NSCLC. Patients treated with dacomitinib demonstrated a median progression-free survival (PFS) of 14.7 months (95% CI, 11.1-16.6) compared with 9.2 months (95% CI, 9.1-11.0) with gefitinib (HR, 0.59; 95% CI, 0.47-0.74; P <.0001).² The median overall survival (OS) with dacomitinib was 34.1 months (95% CI, 29.5-37.7) versus 26.8 months (95% CI, 23.7-32.1) with gefitinib (HR, 0.760; 95% CI, 0.582-0.993; P = .0438), according to updated data presented at the 2018 ASCO Annual Meeting.³

Notably, in patients with EGFR exon 21 L858R mutations, dacomitinib also showed an OS benefit compared with gefitinib (32.5 vs 23.2 months; HR, 0.707; 95% CI, 0.478-1.045; P = .0805).

However, treatment with dacomitinib is associated with increased toxicity compared with gefitinib. In ARCHER 1050, grade ≥3 AEs were observed in 63.0% of patients treated with dacomitinib versus in 41.1% of those treated with gefitinib. Dose reductions of dacomitinib were also necessary in 66% of patients compared with 8% of patients who received gefitinib.

“The key way to move forward from first-generation EGFR TKIs is to look at the pattern of resistance to EGFR TKIs,” Riely said. Importantly, only the third-generation inhibitor osimertinib (Tagrisso), though, is effective in targeting EGFR T790M, which is the dominant mechanism of acquired resistance to prior treatment with an EGFR TKI. Riely noted that osimertinib is also active against the common EGFR L858R and exon 19 deletion mutations, and has slight activity against EGFR wild-type, which would explain for some of the rash and diarrhea seen in patients treated with this TKI.

“Initial treatment with a third-generation EGFR TKI with the ability to not only inhibit T790M, but also the underlying EGFR mutation, leads to significantly longer progression-free survival,” Riely said.

In the FLAURA study of osimertinib in the frontline setting compared with standard EGFR TKIs gefitinib and erlotinib, osimertinib demonstrated a median PFS of 18.9 months (95% CI, 15.2-21.4) compared with 10.2 months (95% CI, 9.6-11.1) with erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P <.001). Immature OS data demonstrated a hint of OS benefit compared with standard EGFR TKIs (HR, 0.63; 95% CI, 0.45-0.88; P = .007).⁴

“Practically, in the clinic, when we’re thinking about this, it helps us in a couple of different ways to start with osimertinib. We don’t have the transition point where we have to biopsy patients to look for T790M and the uncertainty around that. But probably more importantly is the difference in toxicity. Patients who receive osimertinib have a fairly improved toxicity profile compared with patients who receive gefitinib or erlotinib. There’s less rash, [and] there’s less diarrhea,” Riely commented.

References

1. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring 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.
2. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3.
3. Mok T, Cheng Y, Zhou X, et al. Dacomitinib (daco) versus gefitinib (gef) for first-line treatment of advanced NSCLC (ARCHER 1050): Final overall survival (OS) analysis. J Clin Oncol. 2018;36(suppl; abstr 9004).
4. 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.

View more from the 2019 Winter Lung Cancer Conference