TKIs Dominate NCCN Update in EGFR+ NSCLC

Rogerio C. Lilenbaum, MD

Testing for EGFR mutations should be routine in patients with non­—small cell lung cancer (NSCLC). With the presence of an EGFR mutation, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif) are appropriate treatment options.

In patients with sensitizing EGFR mutation­—positive NSCLC who progress on a first- or second-generation tyrosine kinase inhibitor (TKI), the type of progression determines the treatment option.

These were the take-home messages delivered at the 2016 NCCN Annual Conference.¹

Rogerio Lilenbaum, MD, chief medical officer of Smilow Cancer Hospital at Yale-New Haven, discussed first-line management of EGFR-mutated NSCLC, noting that survival is superior for patients with lung adenocarcinoma who receive appropriate therapy for their molecular alteration compared with patients who have wild-type lung cancer or who have molecular alterations but do not receive appropriate treatment.

“EGFR testing should not be limited to patients who have a high probability of having an EGFR mutation. EGFR testing should be done for every patient with a nonsquamous histology,” Lilenbaum said. “It’s important that clinical enrichment is no longer a criterion to guide molecular testing. It should be routine in clinical practice.”

Version 4.2016 of the NCCN NSCLC guideline recommends EGFR testing with or without ALK testing as part of broad molecular profiling. Without information about EGFR testing, treatment should not be initiated with a TKI, Lilenbaum advised. “If you need to treat someone quickly…even if you anticipate a high probability of EGFR mutation, use chemotherapy first, and switch to a TKI when the information comes back.”

Randomized trials in which patients were selected for the presence of EGFR mutation show a consistent advantage to an EGFR TKI as first-line treatment compared with chemotherapy on the endpoints of overall response rate (ORR) and progression-free survival (PFS). Crossover to TKI in these trials compromised the ability to detect an advantage on overall survival (OS), he said. The agents utilized in this setting were erlotinib, afatinib, and gefitinib. Afatinib has demonstrated an OS benefit in patients with del19 mutations.

In a comparison between TKIs as first-line treatment in the LUX-Lung 7 trial, afatinib showed superior rates of ORR, PFS, and time to failure compared with gefitinib.²

In a phase II study (Lancet Oncol. 2014;15[11]:1236-1244) the combination of bevacizumab (Avastin) and erlotinib was associated with significant prolongation of PFS compared with erlotinib alone (16 vs. 9.7 months; HR, 0.54; P = .0015) in patients with activating EGFR mutations (exon19 del, exon21 L858R).

When treated with EGFR TKIs, 70% of patients with activating mutations will have tumor regression, but eventually disease progresses in most patients, at which time they have developed acquired resistance to gefitinib, erlotinib, or afatinib.

The T790M mutation is the common mechanism of acquired resistance to EGFR TKIs. The type of progression drives second-line treatment, said Leora Horn, MD, MSc, clinical director, Thoracic Oncology Research Program, Vanderbilt Ingram Cancer Center.

Patients with systemic disease progression have multiple new lesions and multiple sites of disease. “Those are the patients you definitely want to switch therapy,” she said, whereas for patients with oligoprogression, maintaining their TKI is reasonable.

Some patients progress only in the CNS while their systemic disease remains stable. “At this time, we often will radiate the lesions in the CNS…and continue the patient on their TKI,” although switching to third- or fourth-generation TKIs may eventually prove more effective,” she said.

In the phase 2 ASPIRATION trial, continuing first-line erlotinib in patients with sensitizing EGFR mutation­—positive NSCLC after progression extended PFS by 3 months compared with discontinuation of erlotinib.³ Adding chemotherapy to gefitinib beyond progression failed to improve PFS or OS in the phase II IMPRESS trial.⁴

All patients should have a biopsy to evaluate for T790M prior to switching systemic therapy, advised Horn. In patients in whom a tissue biopsy is not possible, a serum-based test for T790M is reasonable.

Osimertinib (Tagrisso) is a third-generation TKI that is approved for the treatment of patients with EGFR mutation—positive NSCLC treated with a first- or second-generation TKI and who develop a T790M mutation as their method of acquired resistance.

FDA approval of osimertinib was based on the phase II AURA 2 trial⁵ and the AURA extension cohort,⁶ in which median PFS was 9.7 months following a switch to osimertinib in patients who progressed despite 2 lines of prior therapy with at least one being a TKI.

Version 4.2016 of the guideline for management of NSCLC recommends osimertinib or continuation of erlotinib, afatanib, or gefitinib as subsequent therapy upon progression in asymptomatic patients with a sensitizing EGFR mutation. For symptomatic patients, the guideline calls for subsequent therapy based on the site of progression.

References:

1. Lilenbaum R, Horn L. Management of EGFR mutation-positive metastatic non-small cell lung cancer. Presented at: NCCN 21st Annual Meeting; March 30-April, 2016; Hollywood, FL.
2. Park K, Tan E, Zhang L, et al. Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 (LL7). Presented at: 2015 ESMO Asia Congress; Singapore; December 18-21, 2015.Abstract LBA2.
3. Park K, Ahn M, Yu C, et al. ASPIRATION: first-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC. Presented at: 2014 ESMO Annual Meeting; September 26-30, 2014; Madrid. Abstract 12230.
4. Soria J-C, Wu Y-L. Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet. 2015;16:990-998.
5. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.
6. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.

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