NCI-MATCH Phase II: Tolerable TRAEs from Vismdegib Oral Intake

Patients (pts) with solid tumours, lymphomas, or multiple myeloma are being enrolled in the NCI-MATCH (EAY131) platform trial to receive targeted medicines based on matching genetic changes (NCT02465060). Vismodegib (GDC0449) was tested for its anti-tumor effectiveness in patients whose cancers carried the PTCH1 and SMO mutations, as part of Subprotocol Arm T.

Patients were considered for inclusion if their tumours tested positive for SMO or PTCH1 mutations, with results verified by NCI-MATCH central labs. Patients took 150 mg of vismodegib orally, twice daily, for four weeks in a row until progression or toxicity occurred. Every two rounds, tumour response was analysed. Secondary outcomes were progression-free survival, progression-free survival at 6 months, overall survival, and predictive biomarkers. Nevertheless, basal cell carcinomas of the skin were not considered.

33 patients started treatment between 6/20/16 and 9/22/20; 2 were ruled ineligible. Patient characteristics included median age of 64 (range 19-81) and gender distribution of 48.4% female; primary tumour sites/histology of gastrointestinal (n = 9), skin/soft tissue (n = 7), gynecologic (n = 5), lung (n = 4), unknown primary (n = 4), ductal breast (n = 1), and meningioma (n = 1). Additionally, 61.3% (19/31) had received more than three lines of therapy, and 74% ((23/31) > 1 co-occurring mutation [median 2 co-alterations (range 1-20)] . 8/31 > 4 concurrent changes. All 9 patients had SMO mutant tumours; of those, 5 had more than one other genetic change. 22 patients showed changes to PTCH1 (7 SNVs and 15 indels), and 18 also exhibited >1 additional gene alteration. Of the 31 patients whose data could be analysed, 22 were MATCH-confirmed (meaning that central confirmation of tumour PTCH1/SMO mutations was available).

ORR was 9.1% (2/22) among MATCH-confirmed pts and 6.5% (2/31) among all evaluable pts. Patients with skin/soft tissue sarcomas (PTCH) and meningiomas (SMO) each experienced a PR, with the median duration of the response being 14 months. Both MATCH-confirmed and analyzable pts had a median PFS of 1.8 months and a 6-month PFS rate of 22.4%. The median overall survival (OS) for MATCH-confirmed patients was 9.1 months and 7.3 months for evaluable patients. Among the evaluable SMO variations, we recorded 1 PR, 3 SD, 4 PD, and 1 unevaluable response.

One partial response (PR), seven stable (SD), ten PD, and four unidentified (UE) variants were observed among the evaluable PTCH1 variants. Four patients (12.9%) dropped out of treatment because of AE. Of the 33 patients who initiated therapy, 18 (54.5%) experienced toxicity between grades 1-2, and 2 (6.1%) experienced toxicity between grades 1-3. Fatigue (n = 11), anorexia (n = 8), weight loss (n = 7), baldness (n = 7), and dysgeusia (n = 6) were the most frequently reported adverse effects. There were 4 deaths during the research, but they weren’t caused by the int.

Substantial responses were reported in patients with SMOPro641Ala and PTCHGlu947Ter mutations, and vismodegib was well-tolerated with predominantly grade 1-2 toxicities, even though the primary endpoint was not met. Further research on the effects of concurrent molecular alterations may shed light on the mechanisms of response to vismodegib.

Source: https://meetings.asco.org/abstracts-presentations/207874

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02465060

Tsao, A. S., Song, Z., Ho, A. L., Mehnert, J. M., Mitchell, E. P., Wright, J. J., Takebe, N., Gray, R. J., Wang, V., McShane, L., Rubinstein, L. V., Patton, D. R., Williams, P. M., Hamilton, S. R., Conley, B. A., Arteaga, C. L., Harris, L., O’Dwyer, P. J., Chen, A. P., & Flaherty, K. (2022). Phase II study of vismodegib in patients with SMO or PTCH1 mutated tumors: Results from NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol T.. Journal of Clinical Oncology, 40(16_suppl), 3010–3010. https://doi.org/10.1200/jco.2022.40.16_suppl.3010