BLU-667 in RET-driven NSCLC and Thyroid Cancer

An update on the registration-enabling ARROW study

Updated data from the ARROW study with BLU-667 in patients with advanced RET-fusion-positive non-small cell lung cancer (NSCLC) and with RET-altered medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC), demonstrate potent, durable and broad antitumour activity with treatment being well tolerated. Enrolment of the expansion is ongoing with registrational intent. The data were presented at 2019 ASCO Annual Meeting.

RET fusions are targetable oncogenic drivers in up to 2% of NSCLC. RET alterations are targetable oncogenic drivers in approximately 90% of advanced MTC and 20% of PTC. However, no selective RET inhibitors are approved for those indications yet.

BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations, including those that confer resistance to multikinase inhibitors (MKIs). In two abstracts reported at 2019 ASCO Annual Meeting, the investigators provided an update on the registration-enabling ARROW study of BLU-667 in patients with RET-fusion-positive NSCLC and on the expanded experience of BLU-667 in RET-altered thyroid cancer.

The global ARROW study includes dose escalation, DE (30-600 mg daily [QD or BID]) and dose expansion (DX) at the recommended phase II dose (400 mg QD) in patients with advanced, unresetable solid tumours. RET alteration status is determined by local tumour testing. No additional driver mutation is allowed. The patients with ECOG performance status 0 to 1 are included with progressive disease or intolerant to standard of care, or not a candidate. Primary objectives are overall response rate (ORR) per RECIST v1.1 and safety.

BLU-667 in patients with advanced RET-fusion-positive NSCLC

NSCLC patients with RET fusions have not significantly benefited from existing therapy.

The authors reported in the abstract that as of 19 December 2018, 79 patients (21 in DE, 58 in DX) with advanced RET-fusion-positive NSCLC, of whom 44 with KIF5B, 16 with CCDC6, and 19 with other/pending fusion partner received BLU-667.

Median number of prior therapies was 2 (range 0-8) including chemotherapy (76%), immunotherapy (41%), and MKI (27%). In total, 39% had baseline brain metastases.

The ORR among 57 response-evaluable patients with measurable disease and at least one follow-up disease assessment was 56%, of whom 32 partial responses (PR), 9 PR pending confirmation, 20 stable disease (SD), 5 progressive disease (PD). In total 91% (29/32) of responding patients remain on treatment; 6 have achieved response duration ≥ 6 months. Disease control rate (DCR) was 91% (52/57). Among 30 patients at the recommended phase II dose previously treated with platinum chemotherapy, the ORR was 60% (18 PRs; 7 pending confirmation). Responses occur regardless of prior treatment or RET fusion genotypes. Intracranial activity has been observed with shrinkage of brain metastases. In total, 80% of NSCLC patients treated at recommended phase II dose remain on treatment and only 3% discontinued due to related adverse event.

In NSCLC patients, treatment-related toxicity, generally low-grade and reversible (28% had ≥ grade 3 events), included increased AST (22%), hypertension (18%), increased ALT (17%), constipation (17%), fatigue (15%) and decreased neutrophils (15%).

Justin F. Gainor of the Massachusetts General Hospital, Boston, MA, US who presented the results concluded that BLU-667 demonstrated broad and durable antitumour activity in patients with RET-fusion-positive advanced NSCLC. Responses were observed regardless of treatment history, RET fusion partner or CNS involvement. The drug is active against intracranial metastases.

BLU-667 has FDA breakthrough therapy designation in RET-fusion-positive NSCLC that progressed following platinum-based chemotherapy.

Data support expansion of ARROW study in treatment-naïve NSCLC patients and continued enrolment of other RET-altered solid tumour groups.

BLU-667 in patients with advanced RET-altered thyroid cancers

As of 19 December 2018, 60 patients with RET-mutated MTC, of whom 37 with M918T, 8 with C634R/S/W, 4 with V804M, and 11 with other/pending fusion partner and 5 patients with RET-fusion-positive PTC of whom 3 with NCOA4, and 2 with CCDC6 fusion partner received BLU-667; 37 in DE, 28 in DX. In total, 58% had prior MKI therapy.

Among 49 response-evaluable MTC patients, the ORR is 47%; 2 complete responses and 21 PR, 4 PR pending confirmation, 25 SD, 1 PD. In total 96% (22/23) of responding patients continue treatment; 15 with response duration ≥ 6 months. Two of four evaluable PTC patients had PR; all 5 enrolled PTC patients continue treatment at 8-11 months. Responses in MTC occur regardless of MKI resistance (prior cabozantinib/vandetanib: ORR 46% (12/26)) or RET genotype (PR in two of three evaluable patients with V804M). The DCR in MTC patients is 98%.

Rapid plasma clearance of RET variants and marked reduction in CEA and calcitonin is observed.

Treatment-related toxicity in MTC/PTC patients, generally low-grade and reversible (28% had grade 3 events, no grade 4/5 events, no events requiring discontinuation), includes decreased whole blood count (23%), increased AST (17%), increased ALT, blood creatinine, and phosphate, hypertension, and decreased neutrophils (all 15%).

The results were presented in a poster discussion session by Matthew H. Taylor of the Oregon Health & Science University, Portland, OR, US on behalf of study investigators.

BLU-667 activity in other RET-fusion-positive malignancies

The ARROW researchers found also PR in two of two patients with metastatic pancreatic cancer and PR in a patient with intrahepatic bile duct carcinoma treated with BLU-667; the safety profile is similar.

The study authors acknowledged participating patients, study investigators, research coordinators and Blueprint Medicines Corporation.

 

References

Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr 9008).

Taylor MH, Gainor JF, Hu MI-N, et al. Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers. J Clin Oncol 37, 2019 (suppl; abstr 6018).