Practice-Changing Translational Advances Predicted for NSCLC

Mok, who is professor and chair of medicine at the Chinese University of Hong Kong, said that over the past 18 months, study results of second-generation tyrosine kinase inhibitors (TKIs) have shown only modest improvements in progression-free survival (PFS), whereas third-generation TKI osimertinib (Tagrisso) has proven highly effective inT790M-positive disease.

THE CASE FOR SECOND-GENERATION TKIS

Reviewing data from various trials, Mok said second-generation TKIs are not convincingly superior and further study would be helpful. For example, the LUX Lung 3 and 6 trials showed improved median overall survival (OS) forEGFR-positive NSCLC patients treated with afatinib (Gilotrif), amounting to 27.3 months OS versus 24.3 for chemotherapy-treated patients.¹

What really deserves notice, he said, was a significant difference in the effectiveness of afatinib versus chemotherapy in the treatment of patients with an exon 19 deletion, in which he noted a median OS of 31.7 months with afatinib versus 20.7 months with chemotherapy (HR, 0.59; 95% CI, 0.45-0.77;P= .0001).

Mok next turned to the LUX Lung 7 study, a phase IIb, randomized, controlled trial of afatinib versus gefitinib (Iressa) as first-line treatment for patients withEGFR+NSCLC. Independent review showed that the first 10 months of treatment in both arms yielded similar PFS results.²However, at month 18, the PFS rate was 27% in the afatinib arm versus 15% in the gefitinib group (P= .0176). The rates were then 18% versus 8%, respectively, at 24 months (P= .0184). Mok said that it was important to know whether the longer-PFS patients had an exon 19 deletion or simply tolerated their treatment well.

Objective response with gefitinib (56%) was lower in the same study compared with afatinib (70%). But a look at various other studies (IPASS, NEJ002, and WJTOG) showed gefitinib response rates around 70%, leading Mok to ask, “Whom should we trust?”

A look at investigator review data from LUX Lung 7 showed that gefitinib produced an average response rate for patients with exon 19 and 21 deletions in the range of 66%. In the LUX Lung 3 trial, patients with an exon 19 deletion showed a median PFS of 12.7 months for afatinib and 11 months for gefitinib.

Other notable data that are maturing will come from the ARCHER 1050 trial. Fresh results are due out in the first quarter of 2017 on this phase III study, which is comparing the efficacy and safety of first-line dacomitinib with gefitinib in patients with locally advanced or metastaticEGFR+NSCLC (NCT01774721).

TACKLING TKI RESISTANCE

Looking at the management of TKI resistance, Mok discussed the IMPRESS study of gefitinib plus chemotherapy versus placebo plus chemotherapy inEGFR+NSCLC. The goal of the trial was to evaluate the detection rate ofT790Mmutation resistance after first-line gefitinib failure and to study responses inT790Mpatient subgroups.³

In the overall study population, 54.4% of patients wereT790M+and 40.2% wereT790M-negative. The PFS inT790M+patients was similar between the 2 arms. But Mok said there was a difference (6.7 months for gefitinib vs 5.4 months on placebo) in the mutation-negative group that was “interesting.”

OS data from the IMPRESS trial were presented at the 2016 ESMO Annual Congress. ForT790M+patients, OS was 10.8 months for the gefitinib arm versus 14.1 months on placebo. However, OS rates were similar between the 2 arms in theT790M— group (21.4 months for gefitinib vs 22.5 months for placebo).⁴

Osimertinib received preliminary approval by the FDA in November 2015 for patients withEGFR T790M+NSCLC. Results from the phase III AURA 3 study could be significant for this therapy (NCT02151981).

AstraZeneca announced in July 2016 that osimertinib demonstrated superior PFS compared with the standard platinum-based doublet chemotherapy in patients withEGFR T790M+ locally advanced or metastatic NSCLC whose disease had progressed following first-line EGFR TKI therapy. Formal results are expected in December, which Mok expects will be “practice-changing.”

SEEKING OUTT790M+PATIENTS

Mok said that oncologists should consider it an obligation now to test forT790Min all patients who progress on first-line EGFR TKI treatment. The AURA 1 study⁵showed that the plasma cell-free DNA (cfDNA) test had high sensitivity and specificity forT790M, but he noted that false-positives were high at 31% forT790M. Even so, the tumor-positive group had a response rate of 62% and the plasma-positive group had a 63% response rate, so “at least doctors can tell a patient who is plasma-positive that they will get a response from osimertinib.”

Further analysis of AURA 1 data showed that of 18 “false-positive patients,” 14 were truly positive. Such results beg the question of what happens to patients who are plasma-positive and tumor-negative, Mok said. “Are they truly false-positive?”

Mok noted that plasma cfDNA testing is delivering highly reliable results and is ready for mainstream usage. The Cobas 4800 plasma ctDNA test, for example, earned praise from Mok, who considered it paradigm-shifting based on strong results.

REFERENCES

Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.Lancet Oncol. 2015;16(2):141-151. doi: 10.1016/S1470-2045(14)71173-8.

Hirsh V, Yang JC-H, Tan E-H, et al. First-line afatinib (A) vs gefitinib (G) for patients (pts) with EGFR mutation positive (EGFRm+) NSCLC (LUX-Lung 7): patient-reported outcomes (PROs) and impact of dose modifications on efficacy and adverse events (AEs).J Clin Oncol. 2016;34(suppl; abstr 9046).

Soria JC, Wu YL, 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 Oncol. 2015;16(8):990-998. doi: 10.1016/S1470-2045(15)00121-7.

Soria J, Kim S, Wu Y, et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): Final overall survival (OS) analysis. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1201O.

Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell Lung Cancer.J Clin Oncol.2016;34(28):3375-3382. doi: 10.1200/JCO.2016.66.7162.