Targeted therapies for non–small cell lung cancer (NSCLC) are a hotbed of investigation. Two new targeted therapies are promising for patients with lung tumors that are either EGFR exon 20 insertions or RET-rearranged. At the 2019 ASCO Annual Meeting, attendees heard early data on therapies targeted to these complex driver alterations.

In the first study, TAK-788 achieved a confirmed objective response rate of 43% and a disease control rate of 86% in pretreated patients with advanced NSCLC and EGFR exon 20 insertions.¹ Responses were seen in patients with and without brain metastases at baseline.

The second study found that BLU-667 yielded an objective response rate of 58% and a disease control rate of more than 90% in patients with RET fusion–positive advanced NSCLC.² In patients who received prior platinum-based chemotherapy, the overall response rate was 60%, and the disease control rate was 100%.

TAK-788: Study Details

“EGFR mutations are relatively common in patients with lung cancer. Exon 20 is the third most common alteration in EGFR, and unlike exons 19 and 21, it is associated with resistance to available tyrosine kinase inhibitors [TKIs] used to treat NSCLC,” explained Gregory J. Riely, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, who was filling in for lead author Pasi Jänne, MD, in presenting the data. “TAK-788 has potent and selective preclinical inhibitory activity against EGFR exon 20 insertions compared with other TKIs such as afatinib and osimertinib,” he noted.

Gregory J. Riely, MD, PhD

Pasi Jänne, MD

For phase II, the recommended dose carried forward from phase I was 160 mg/d. Of 7 phase II cohorts with different disease characteristics, Dr. Riely presented efficacy data on cohort 1 alone, which comprised 28 patients treated at the 160-mg/d dose: 22 from the dose-expansion phase and 6 from the dose-escalation phase. Safety data were presented for 2 cohorts: 137 patients ever treated with TAK-788 and 72 patients treated at 160 mg/d across all cohorts.

In cohort 1, the median patient age was 62 years; 79% had an Eastern Cooperative Oncology Group performance status of 1; 43% had brain metastases at baseline (largest tumor allowed was up to 1 cm); the median number of prior systemic anticancer regimens was three (including prior checkpoint inhibitors in 61% and EGFR- or HER2-directed TKIs in 18%).

The median time on treatment was 7.9 months. Seven patients had progressive disease, three patients discontinued treatment due to an adverse event, three patients discontinued treatment due to physician’s decision, and one patient died. “About half the patients are still on study, including those with brain metastasis,” Dr. Riely noted.

At the time of data cutoff, the best radiographic response in patients with EGFR exon 20 inserts was 43%; 12 were confirmed responses and 3 were unconfirmed responses.

The confirmed objective response rate in patients with baseline brain metastases was 25%, with a disease control rate of 67%. In patients without baseline brain metastases, the objective response rate was 56%, and the disease control rate was 100%. Median progression-free survival in cohort 1 was 7.3 months (3.7 months for patients with brain metastases at baseline and 8.1 months for those without brain metastases at baseline). “Patients with brain metastases had lower response rates and shorter progression-free survival,” Dr. Riely said.

TAK-788: Safety

Grade 3 or higher treatment-emergent events occurred in 63% of patients treated at the 160-mg dose and in 61% of those who received the drug at any dose; 25% required dose reductions for treatment-related adverse events, and 14% discontinued therapy.

The most common adverse events were grade 1 and 2. The most common grade 3 or higher adverse events were diarrhea (18%), nausea (6%), increased lipase (6%), stomatitis (4%), and increased amylase (4%).

“Treatments such as EGFR TKIs [afatinib, osimertinib] have limited potency against exon 20 insertion variants. Another drug in development, poziotinib, has limited selectivity for exon 20 compared with TAK-788,” Dr. Riely said.

TAK-788 is being studied further. The EXCLAIM expansion cohort (using TAK-788 at 160 mg/d) is currently ongoing in patients with locally advanced or metastatic NSCLC with exon 20 insertion mutations. The planned enrollment is 91 patients.

Background on RET Inhibitors

“BLU-667 is a highly potent and selective RET inhibitor under study in patients with advanced RET fusion–positive NSCLC,” explained lead author Justin F. Gainor, MD, of Massachusetts General Hospital, Boston.

Justin F. Gainor, MD

Genetic alterations in RET drive the pathogenesis of various solid tumors, including lung, thyroid, esophageal, and breast cancers as well as melanoma, he noted. About 1% to 2% of lung cancers harbor RET fusion, and there is no approved RET inhibitor to date. Although available TKIs may include RET fusion as an off-target effect, they are not selective for it.

Two selective RET inhibitors have been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration: BLU-667 and LOXO-292. BLU-667 is designed to inhibit RET alterations and resistance mutations. It is 90-fold more selective for RET than for VEGFR2, a common target of earlier multikinase inhibitors.

BLU-667: Study Details

The ongoing ARROW study is currently enrolling patients into seven cohorts. The data Dr. Gainor presented were based on cohorts 1 and 2, which included 131 RET fusion–positive patients: 41 platinum-naive and 90 previously treated with platinum. The safety analysis was based on 120 patients.

Forty percent of patients in cohort 1 had brain metastases at baseline. These patients were heavily treated, with a median of two prior lines of therapy (chemotherapy, 77%; checkpoint inhibitor, 39%; and multikinase inhibitor, 18%). The most common fusion

partner was KIF5B (66%). A majority of responses were seen on the first scan, and 82% remain on treatment as of the data cutoff of April 2019. The median duration of response has not yet been reached, and many patients continue to respond for more than 24 months, Dr. Gainor said. Responses occurred regardless of the RET fusion partner, brain metastases, and prior front-line therapy.

Among nine patients with measurable untreated brain metastases, 78% had tumor shrinkage, including tumors that had CCDC6 and KIF5B as fusion partners. No patient experienced disease progression due to new central nervous system involvement. Dr. Gainor showed scans of two patients, one with complete resolution, and the other with near-complete resolution of brain metastases on treatment with BLU-667.

Treatment-related toxicity was generally low-grade and reversible; the adverse events included constipation, neutropenia, fatigue, hypertension, and alanine transaminase elevation. Grade 3 neutropenia was reported in 13% and grade 3 hypertension, in 10%. Treatment discontinuation due to treatment-related toxicity was reported in 7%.

“BLU-667 has activity in other RET fusion–positive malignancies, including genitourinary and papillary thyroid cancers,” Dr. Gainor said. “The broad and durable activity of BLU-667 in patients with RET fusion–positive NSCLC supports the expansion of the ARROW trial and studies in other malignancies.” ■

DISCLOSURE: Dr. Riely has received institutional research funding from Novartis, Roche/Genentech, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals, Mirati Therapeutics, Merck, and Takeda; has received travel expenses from Merck Sharp & Dohme; and has submitted a patent application for the pulsatile use of erlotinib to treat or prevent brain metastases. Dr. Gainor has received honoraria from Merck, Incyte, Ariad, Novartis, Pfizer, and Takeda; is a consultant/advisor for Genentech, Bristol-Myers Squibb, Theravance, Loxo, Takeda, Array BioPharma, Amgen, Merck, Agios, Regeneron, Oncorus, Jounce Therapeutics, and Blueprint Medicines; has received institutional research funding from Merck, Novartis, Genentech, Bristol-Myers Squibb, Adaptimmune, AstraZeneca, Ariad, Jounce Therapeutics, Blueprint Medicines, Moderna Therapeutics, Tesaro, Alexo Therapeutics, and Array BioPharma; and has an immediate family member who is an employee of Ironwood Pharmaceuticals.

REFERENCES

1. Jänne PA, Neal JW, Camidge DR, et al: Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. 2019 ASCO Annual Meeting. Abstract 9007. Presented June 3, 2019.

2. Gainor JF, et al: Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor in patients with advanced RET-fusion+ non-small cell lung cancer. 2019 ASCO Annual Meeting. Abstract 9008. Presented June 3, 2019.