New Therapies Intriguing for Elusive Targets in NSCLC

Silas Inman @silasinman
Published: Tuesday, Jun 04, 2019

Christine M. Lovly, MD, PhD
Christine M. Lovly, MD, PhD
Two new therapies are showing encouraging findings for patients with non–small cell lung cancer (NSCLC) with either RET rearranged or EGFR exon 20 insertions, raising hope that 2 hard-to-target driver alterations may soon have an associated targeted treatment, noted ASCO discussant Christine M. Lovly, MD, PhD, at the 2019 ASCO Annual Meeting.

In the first study,1 TAK-788 demonstrated a confirmed objective response rate (ORR) of 43% (95% CI, 24%-63%) and a disease control rate (DCR) of 86% (95% CI, 67%-96%) for patients with EGFR exon 20 insertions. The confirmed ORR consisted of 12 partial responses (PRs), with an additional 3 PRs that were not yet confirmed by a second scan.

In the second early stage study,2 BLU-667 showed an ORR of 58% (95% CI, 43%-72%) for patients with RET fusion-positive advanced NSCLC, with a DCR of 96% (95% CI, 86%-99%). In those treated with prior platinum-based chemotherapy, the ORR was 60% (95% CI, 42%-76%) with a DCR of 100% (95%, 90%-100%).

“These are not new targets...but they are complex targets. These are not targets that are necessarily easy to build drugs against,” said Lovly, from Vanderbilt-Ingram Cancer Center. “EGFR exon 20 insertions are quite heterogenous at the molecule level. Likewise, RET alterations are another complex target that are very heterogenous at the molecular level."

TAK-788 for EGFR Exon 20

Exon 20 is the third most common alteration in EGFR, following exon 19 and exon 21, which are successfully targeted by other TKIs. Despite efficacy in other types of activating mutations, TKIs are largely ineffective for those with insertions in exon 20.

TAK-788 was examined in a multi-cohort phase I/II trial for patients with advanced NSCLC with different disease characteristics. In a dose escalation phase of the study, the maximum tolerated dose was determined to be 160 mg daily. Twenty-eight patients from the trial who were treated with 160 mg were analyzed for the presentation at the ASCO meeting (22 from cohort 1 and 6 from the dose escalation). Safety data were available for 137 patients across all cohorts treated at various doses, and specifically for 72 patients who received the 160 mg dose across all cohorts.

Forty-three percent of patients in this analysis had brain metastases at baseline. The median age of patients was 62 years, and the most common ECOG status was 1 (79%). The median number of prior systemic cancer regimens was 3, including prior checkpoint inhibitors (61%) and EGFR- or HER2-directed TKIs (18%).

The confirmed ORR was 25% in patients with baseline brain metastases, with a DCR of 67%. In those without brain metastases, the confirmed ORR was 56% and the DCR was 100%. The median progression-free survival (PFS) was 7.3 months across all patients in the analysis and was 3.7 months and 8.1 months for those with and without brain metastases, respectively.

“The numbers are small here, so it is difficult to divide out too many subsets,” cautioned senior study author Gregory J. Riely, MD, from the Memorial Sloan Kettering Cancer Center. “But if you compare patients with baseline brain metastases to those without baseline brain metastases there is a numerically lower response rate in those with baseline brain metastases as well as a shorter progression-free survival.”

Grade ≥3 treatment-emergent adverse events (AEs) occurred in 63% of patients treated at the 160 mg dose across cohorts and in 61% of those treated with TAK-788 at any dose. Grade ≥3 treatment-related AEs occurred in 40% and 32% of patients in the 160 mg and any dose arms, respectively. The most common treatment-related grade ≥3 AEs in at the 160 mg dose were diarrhea (18%), nausea (6%), increase lipase (6%), stomatitis (4%), and increased amylase (4%).

Another therapy in development, poziotinib, has also shown potential for patients with EGFR exon 20 insertions, according to findings presenting at the IASLC 19th World Conference on Lung Cancer.3 This therapy induced a confirmed ORR of 43% among evaluable patients with EGFR exon 20 mutant NSCLC.

“Treatment with available EGFR TKIs, like afatinib or osimertinib, have limited potency for EGFR exon 20 insertion variants,” Riely said. “Poziotinib has limited selectivity when you compare the EGFR exon 20 versus EGFR wild-type. TAK-788 potently inhibits EGFR exon 20 mutations and there is some selectivity over wild-type EGFR.”

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