Third-Generation EGFR TKIs Move to Frontline in Lung Cancer

David Planchard MD, PhD

EGFR TKIs, such as erlotinib, afatinib, and gefitinib, have become the lynchpin of first-line targeted treatment of EGFR-mutated lung cancer. Their use is supported by data from several studies showing substantial improvements versus chemotherapy. Now, a new generation of TKIs are poised to take their position, according to David Planchard MD, PhD.

“Drug resistance limits the long-term success of even the most effective targeted therapies,” according to Planchard, from the Department of Cancer Medicine at the Institute Gustav Roussy in Villejuif, France, during the 2016 European Lung Cancer Conference (ELCC).

“Third-generation TKIs offer a higher level of selectivity towards EGFR versus wild type, allowing a wider therapeutic range, and a better tolerability profile,” he said. “Expect a prolonged control of the disease compared to currently available TKIs.”

Planchard described the odyssey of treatments for patients with EGFR-mutated lung cancer who develop resistance to frontline TKIs, usually a result of acquired resistance through the T790M mutation. This has led to the development of third-generation TKIs that selectively bind to EGFR T790M mutations, such as osimertinib (Tagrisso) and rociletinib. Pretreated patients with T790M-positive tumors have experienced a median progression-free survival (PFS) of 9.7 to 11 months with osimertinib at 80 mg and 8.0 months with rociletinib at 625 mg.

Planchard offered the possibility that the best sequence may actually be to reverse these lines of therapy and to start with a third-generation TKI.

“Prevention or delay of resistance may be a better strategy than treating resistance,” he said and detailed a strategy of ‘hitting harder’ the EGFR mutation target with third-generation TKIs.

Planchard proceeded to make a strong case for T790M inhibition in the first-line, explaining that this strategy inhibits mutant EGFR with sensitizing mutation exon 19 or L858R, as well as dual mutant EGFR having either de novo or secondary T790M resistance mutation. Third-generation TKIs have the advantage of greater selectivity, better tolerability, and also allow for optimized brain penetration. They have demonstrated longer PFS and prolonged the development of resistance, according to Planchard.

With available EGFR first-generation TKIs, rash and diarrhea have been observed in approximately 80% of patients with grade 3/4 seen in nearly 20% of patients. In contrast, osimertinib has shown low rates of all-cause adverse events (AEs) in phase I and II trials. Similar findings were seen with rociletinib, in which grade 1 or 2 diarrhea was noted in 20% of patients, with no reports of diarrhea of grade 3 or higher.

Third-generation TKIs show optimized brain penetration, and are therefore more likely to have activity in brain metastases, which develop within a year of treatment in many patients. Planchard also cited a case study from his practice demonstrating tumor shrinkage in the brain of a patient with lung cancer and said that phase II trial data have shown efficacy in patients with a history of brain metastases.

Osimertinib has been evaluated as first-line treatment in the AURA trial in patients with locally advanced or metastatic EGFR-mutated NSCLC. Thirty patients each received 80 mg per day and 160 mg per day in the first-line setting. At median follow-up of 16.6 months, the ORR was 77%. Median PFS was 19.3 months for the 160-mg dose and has not yet been reached for the 80 mg-dose.

Osimertinib was well tolerated at both dose levels, though at the recommended 80-mg dose, just 10% of patients required dose reduction and no grade 3 or higher AEs of rash, diarrhea, and other AEs were reported; there was one report of grade 3 nausea.

Planchard pointed out that first-line osimertinib will be evaluated in the FLAURA study and the phase III SOLAR study (NCT02588261). He also noted that the clinical development of rociletinib is ongoing in the TIGER-X, -1, -2, and -3 trials.

Possible pitfalls of first-line third-generation TKIs could be the type of resistance that develops. The C797S mutation is known to impact the sensitivity of these treatment strategies, as it blocks the binding site of osimertinib. Also, the magnitude of PFS and overall survival response is unknown.

“Tumor heterogeneity has important clinical implications and may also enter into the equation,” Planchard commented.

Combination treatment may be the way forward to counter this pitfall. Osimertinib in combination or alternating with gefitinib as first-line in patients with EGFR-mutant lung cancer is currently being evaluated. Co-targeting EGFR and MEK has shown prolonged time to the development of resistance.

Another strategy being tested is the inhibition of anti-apototic factors BCL-xL and BCL-2.

Other combination strategies have shown promising activity, as in the TATTON trial of osimertinib plus durvalumab, a high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. This study was conducted in patients with confirmed T790M mutations but was offset by elevated incidence of pneumonitis.

With all these new options and possibilities for combinations, Planchard said, toxicity must remain top-of-mind for physicians and researchers alike.

“Toxicity represents another pitfall of new treatment strategies and must be minimized in treating patients.”

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