Should EGFR TKI Use Expand in Frontline NSCLC?

Zosia Piotrowska, MD, MHS

Treatment with osimertinib (Tagrisso) in the frontline has been the standard of care for patients with EGFR-mutant non—small cell lung cancer (NSCLC) since the pivotal FLAURA trial. However, more work is needed to introduce first- and second-generation TKIs both alone and in combination to improve the treatment landscape, according to Zosia Piotrowska, MD, MHS.¹

“The question today is, ‘Should we add EGFR TKI to newly diagnosed patients?’ But I think the question should be, ‘Should we add EGFR TKI to all newly diagnosed patients?’” said Piotrowska, instructor at Harvard Medical School and medical oncologist at Massachusetts General Hospital, at the start of her presentation at the 17th Annual Winter Lung Cancer Conference^®.

There are 5 available EGFR TKIs for the treatment of patients with EGFR-mutant lung cancers: gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif), dacomitinib (Vizimpro), and osimertinib.²

The phase III FLAURA trial (NCT02296125) randomized patients with EGFR-mutant NSCLC to receive either osimertinib or comparator EGFR TKIs gefitinib and erlotinib. The median progression-free survival (PFS) was 18.9 months with osimertinib versus 10.2 months with erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P <.001). Based on these data, osimertinib became the first third-generation EGFR TKI approved for this patient population and became accepted as the standard of care for newly diagnosed patients harboring an EGFR mutation.³

An updated analysis presented by Ramalingam et al at the 2019 ESMO Congress demonstrated improved overall survival (OS) with osimertinib over the first-generation EGFR TKIs (38.6 vs 31.8 months; HR, 0.799; 95% CI, 0.641-0.997; P = .0462).³

“But now when patients progress on osimertinib, what we are seeing is that it is getting harder and harder to target resistance mechanisms,” Piotrowska said. “This begs the question, ‘Can we be better? Can we improve upon our first-line therapy such that we can delay the time that we get to resistance?’”

This question is at the forefront of the development of 3 potential combination strategies for patients.

TKI Plus Chemotherapy

Approximately 20% to 30% of patients with EGFR-mutant NSCLC do not make it to second-line therapy. “Despite our best efforts, we know that many of our patients do not make it to second-line therapy, but we also know that chemotherapy is a very good treatment [option] for these patients, they really do well with chemotherapy,” Piotrowska said. “To see these patients not getting to that point is sobering.” Moving chemotherapy earlier in treatment for patients may improve therapeutic benefit for those who might otherwise progress following standard of care osimertinib.

Two independent phase III trials examined gefitinib plus chemotherapy in treatment-naïve patients. The Japanese NEJ009 trial showed a median OS of 52.2 months when adding gefitinib to carboplatin/pemetrexed (Alimta) versus 38.8 months with chemotherapy alone (HR, 0.695; 95% CI, 0.520-0.927; P = .013).⁴ A second study conducted in India (Noronha Study) also examined gefitinib combined with pemetrexed/carboplatin compared with gefitinib alone. Results demonstrated a median OS of not reached versus 17 months with the combination versus monotherapy, respectively (HR, 0.45; 95% CI, 0.31-0.65; P < .0001).⁵

“What we don’t know is how to interpret this data in the setting of having osimertinib,” Piotrowska said, adding that the upcoming FLAURA2 study will seek to answer that clinical question. FLAURA2 (NCT04035486) will enroll 586 patients to osimertinib with or without chemotherapy as first-line therapy.

TKI Plus Anti-VEGF Therapy

Preclinical data suggest that dual blockade of EGFR and VEGF pathways may be synergistic and studies have shown improved PFS with the EGFR TKI and anti-VEGF combination.

The phase III Japanese NEJ026 trial randomized 228 patients to erlotinib plus bevacizumab (Avastin) versus erlotinib alone. Data showed an improved median PFS from 13.3 months with monotherapy to 16.9 months with the combination (HR, 0.605). The OS data are not yet mature.⁶

A second phase III study (RELAY; NCT02411448) compared ramucirumab (Cyramza) plus erlotinib versus erlotinib plus placebo in previously untreated patients with EGFR-positive NSCLC. Again, improved PFS was seen in the combination arm versus the placebo arm (19.4 vs 12.4 months; HR, 0.591) and the OS data are not yet mature.⁷

“This is exciting data and it is encouraging, but I don’t think we are routinely using VEGF antibodies in our clinical practice and I think the reason for that is all of these studies came out in an era where we already had the FLAURA data and we already had moved on to osimertinib as first-line therapy,” Piotrowska noted.

Studies seeking to answer this clinical question include the upcoming phase III EA5182 study (NCT04181060) examining osimertinib plus bevacizumab versus osimertinib alone. “I think this has the potential to change practice and I look forward to seeing the results,” Piotrowska said.

Combining EGFR TKIs

A final area of exploration is the combination of 2 EGFR TKI agents. T790M is the most common resistance mechanism observed in patients who progress following treatment on erlotinib and gefitinib. Osimertinib was developed to combat this resistance, however patients acquire an additional EGFR mutation, C797S, following treatment with the third-generation agent.⁸

“The thought is if we combine these 2 drugs together neither one of these mutations alone will be enough to allow resistance to develop and perhaps that will induce more durable response,” Piotrowska said.

Several phase I and II studies represent the tip of the iceberg in this space. For example there is a trial exploring osimertinib plus gefitinib (NCT03122717) and one exploring osimertinib plus dacomitinib (NCT03810807). Additionally, a phase II study (NCT03292133) is examining another third-generation EGFR inhibitor, nazartinib, together with gefitinib.

Identification of patients who will benefit from treatment with the combination versus those more likely to experience a greater response from osimertinib monotherapy is another area for exploration, Piotrowska concluded. Areas for future research will include the impact of co-mutations, ctDNA clearance, and the depth of radiographic response for newly diagnosed patients.

References

1. Piotrowska Z. Should we add EGFR TKIs in newly diagnosed patients? Presented at: 17th Annual Winter Lung Conference; February 7-9, 2020; Miami Beach, FL.
2. Takeda M, Nakagawa K. First- and second-generation EGFR-TKIs are all replaced to osimertinib in chemo-naive EGFR mutation-positive non-small cell lung cancer? Int J Mol Sci. 2019;20(1):E146. doi: 10.3390/ijms20010146.
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi: 10.1056/NEJMoa1913662.
4. Nakamura A, Inoue, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol. 2018;35(suppl 15; abstr 9005). doi: 10.1200/JCO.2018.36.15_suppl.9005.
5. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2019;38(2):124-136. doi: 10.1200/JCO.19.01154.
6. 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.
7. Nakagawa K, Garon EB, Seto T, et al; 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.
8. Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 2015;21(17):3924-33. doi: 10.1158/1078-0432.CCR-15-0560.

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