Upfront EGFR TKI Questions Remain in NSCLC

Benjamin P. Levy, MD

Multiple options currently exist for patients with EGFR-positive non—small cell lung cancer (NSCLC), with additional therapies on the horizon, making upfront treatment selection an increasingly difficult endeavor, Benjamin P. Levy, MD, explained during the 10th Annual New York Lung Cancer Symposium.

“First- and second-generation TKIs have led to similar improvements in outcomes,” said Levy, medical director of Thoracic Medical Oncology for Mount Sinai Health Systems. “It will be very interesting to see how T790M inhibitors do up front; I also look forward to the erlotinib and bevacizumab story to see if this is a treatment strategy that could perhaps improve outcomes.”

A host of phase III clinical trials have assessed the various EGFR TKIs as frontline therapies for patients with NSCLC. Across these studies, the median progression-free survival (PFS) ranged from 8 months with gefitinib (Iressa) to 13.7 months with erlotinib (Tarceva). Overall survival (OS) in these trials ranged from 2 years to 3 years. However, given the varying patient populations, Levy advised against cross-study comparisons.

“We are looking at different patients from different regions. It's hard to gleam anything from this, other than that these drugs outperformed chemotherapy,” Levy said. “We need to remember that erlotinib, gefitinib, and afatinib are very active agents for our EGFR-positive patients.”

With similar efficacy, the next deciding factor has traditionally been adverse events (AEs); however, this has also proven to be an ineffective determining point. The level of rash, diarrhea, and paronychia were similar between TKIs, with slightly more of each seen in the afatinib (Gilotrif) trials, Levy noted.

To help illuminate differences in these agents, mutational analyses have hinted at varying levels of efficacy between exon 19 deletions (Del19), exon 21 L858R substitutions, and other EGFR mutations. To this point, in the LUX-Lung 3 and 6 trials, afatinib appeared to have greater efficacy among patients with Del19 alterations compared with other mutations.¹

“EGFR mutations are not all the same,” said Levy. “There are subtypes of EGFR mutations that are biologically distinct, and that may impact what we do in the first line.”

In a combined mutation analysis of the LUX-Lung 3 and 6 studies, those with Del19-positive NSCLC experienced a median OS of 31.7 months with afatinib versus 20.7 months with chemotherapy (HR, 0.59; P = .0001). However, in the L858R arm, the median OS with afatinib was 22.1 versus 26.9 months with chemotherapy (HR, 1.25; P = .16).

To answer whether this phenomenon is a byproduct of afatinib or added sensitivity in the Del19 population, numerous retrospective analyses were conducted on existing data from studies of other TKIs. Across these examinations, EGFR TKIs were found to be more effective in patients with alterations in Del19.

In the analysis of 7 trials of EGFR TKIs versus chemotherapy,² a 50% greater benefit was seen with a TKI in the Del19 group compared with L858R substitutions. The hazard ratio in the Del19 group for a TKI versus chemotherapy was 0.24 compared with 0.48 for those with L858R substitution (P < .001).

“What we found in this meta-analysis was that the relative benefit of TKIs was much more pronounced—no matter which TKI was used—in Del19,” said Levy. “Del19 may just happen to be an explicitly susceptible subtype of EGFR mutations, no matter which TKI you give, which may explain the survival advantage seen with afatinib.”

To help answer linger questions regarding differences in TKIs, the phase IIb LUX-Lung 7 trial is currently comparing gefitinib to afatinib as a frontline therapy for patients with EGFR-mutant NSCLC. The trial is specifically looking at patients with Del19 or L858R alterations, with results anticipated in December 2015, according to Levy.

“There are a lot of questions left—more questions than answers,” he said. “LUX-Lung 7 is looking at more than 300 patients. I'm very curious to see these results.”

Outside of trials exploring monotherapy, combination strategies have also been studied, with impressive findings demonstrated by adding bevacizumab (Avastin) to erlotinib.³

In patients with chemotherapy-naive EGFR-positive NSCLC, the combination showed a PFS of 16 months compared with 9.7 months with erlotinib alone (HR, 0.54; P = .0015). Similar sensitivity was seen in those with Del19 alterations, with a median PFS for the combination of 18 months versus 10.3 months with erlotinib alone (HR, 0.41).

“There was an impressive PFS improvement in the study; we don't know the OS advantage yet,” Levy said. “If we look again at Del19 versus L858R, we begin to see the same story start to unravel. Del19 seems to be a more sensitive cohort.”

Following progression on a frontline EGFR TKI, two novel agents are currently pending a decision from the FDA for patients with an acquired T790M resistance mutation. The first agent, rociletinib (CO-1686), showed an objective response rate (ORR) of 60% at the recommended 500 mg dose. The second therapy, osimertinib (AZD9291), showed a 71% ORR.

“Based on their use and clinical trials, these agents are going to be firmly cemented into the treatment paradigm for EGFR-positive patients, specifically in the refractory setting,” Levy said. “The question becomes, can we use these drugs initially?”

Phase III studies are currently enrolling patients to compare these agents to current standard TKIs in the frontline setting. The FLAURA trial will compare osimertinib with gefitinib or erlotinib as a frontline therapy for EGFR-positive NSCLC (NCT02296125). The phase II/III TIGER-1 trial is comparing rociletinib with erlotinib for patients untreated EGFR-mutant NSCLC (NCT01466660).

References

1. Yang J C-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). J Clin Oncol. 2014;32:5s (suppl; abstr 8004^).
2. Lee CK, Wu Y-L, Ding PN, et al. Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis [published online April 20, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.58.1736.
3. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236—1244.

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