Mok Predicts Practice-Changing Translational Advances in NSCLC


Tony Mok, MD, discussed translational advances on the horizon in non-small cell lung cancer during a presentation at the 2016 International Lung Cancer Congress.

Tony Mok, MD

Several practice-changing developments are on the horizon in non—small cell lung cancer (NSCLC), according to Tony Mok, MD, who discussed translational advances in the field at the 2016 International Lung Cancer Congress.

Mok, who is professor and chair of medicine at the Chinese University of Hong Kong, said that over the past 18 months, studies of second-generation tyrosine kinase inhibitors (TKIs) have shown only modest improvements in progression-free survival (PFS), whereas the third-generation TKI osimertinib (Tagrisso) has proven highly effective in T790M-positive disease.

He said plasma cfDNA testing is delivering highly reliable results and is ready for mainstream usage. Meanwhile, strong PFS results for alectinib (Alecensa) versus crizotinib

(Xalkori) in the J-ALEX phase III trial indicate a potential practice-changer. However, Mok cautioned that upcoming results from the ALEX phase III trial (NCT02075840) are essential to confirm efficacy in CNS metastasis control.

In addition, in his discussion of genomic profiling tests, Mok said that costs remain prohibitively high in cases of treatable uncommon mutations in NSCLC.

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) for afatinib (Gilotrif)-treated patients of 27.3 months versus 24.3 for chemotherapy-treated patients, a difference Mok described as “not too intriguing.”

What really deserves notice, he said, was a “significant difference” in the effectiveness of afatinib versus chemotherapy in the treatment of patients with exon 19 deletion, whom he noted had median overall survival of 31.7 months with afatinib versus 20.7 months with chemotherapy (HR, 0.59; CI 95%, 0.45-0.77; P = .0001). Mok said that raises the question whether the finding is true or not, and whether the evidence is strong enough to consider afatinib a second generation TKI.

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

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

A look at investigator review data from LUX Lung 7 showed that gefitinib produced an average response rate for exon deletions 19 and 21 in the range of 66%.

In the LUX Lung 3 trial, the OS data on exon 19 showed a median PFS of 12.7 months for afatinib and 11 months for gefitinib. “So, would overall survival be different? I don’t know about that, but it will come out in ESMO 2016.”

Mok said other notable data that are maturing will come from ARCHER 1050. Fresh results are due out in the first quarter of 2017 on the phase III study, which is comparing the efficacy and safety of first-line dacomitinib with gefitinib in patients with locally advanced or metastatic EGFR-positive NSCLC.

In a look at managing TKI resistance, Mok discussed the IMPRESS study of gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-positive NSCLC. The goal of the trial was to evaluate the detection rate of T790M mutation resistance after first-line gefitinib failure and to study IMPRESS’s primary outcome according to T790M patient subgroups.

In the overall study population, 54.4% of patients were T790M positive and 40.2% were T790M negative. The PFS in T790M-positive patients was similar between the 2 arms.

But Mok said that in the mutation-negative group there was a difference (6.7 months for gefitinib vs 5.4 months on placebo) that was “interesting.” The OS data will be available at ESMO 2016. He said that with the survival benefit of gefitinib in this population unclear, it’s better not to extend therapy, and instead to wait for ESMO 2016, when he will present the findings.

Mok noted that osimertinib was approved by the FDA in November 2015 for patients with EGFR T790M—positive NSCLC and that although this was only a preliminary approval, osimertinib results from the phase III AURA 3 study could be practice-changing.

AstraZeneca announced in July 2016 that osimertinib demonstrated superior PFS compared to standard platinum-based doublet chemotherapy. Osimertinib was tested as a second-line treatment in more than 400 patients with EGFR T790M-positive locally-advanced or metastatic NSCLC whose disease had progressed following first-line EGFR TKI therapy. Formal results are expected in December and Mok said that the data will be positive and most likely “practice-changing.”

He said oncologists should consider it an obligation now to test for T790M in all patients who progress on first-line EGFR TKI treatment. Mok said the AURA 1 study showed that the plasma cfDNA test had high sensitivity and specificity for T790M, but he noted that false-positives were high at 31% for T790M, which he described as “a bit scary.” Even so, he said, 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.”

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

The Cobas 4800 plasma ctDNA test earned praise from Mok, who said he considered it practice-changing based on strong results.

Finally, the J-ALEX phase III trial stands out for its primary endpoint PFS data which, Mok described as “transcendentally different.” At 24 months, the median PFS was not yet reached in the alectinib group versus 10.2 months for the crizotinib arm (HR, 0.34; 99.68% CI, 0.17-0.71; P <.0001).

But Mok said CNS control remains unclear and that further results due from ALEX would help resolve the debate. “Understanding the endpoint in time to CNS progression was not well captured in J-ALEX,” he said, adding that he remains confident that the findings will be practice-changing.


View more from the 2016 International Lung Cancer Conference

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