Senthil Damodaran, MD of MD Anderson talks about the common questions he receives about the Phase II study of copanlisib in patients with tumors with PIK3CA mutations (PTEN loss allowed): NCI MATCH EAY131-Z1F.
NCI-MATCH (EAY131) is a platform study in which patients (pts) with solid tumors, lymphomas, or multiple myeloma are enrolled in targeted therapies based on subsequent genomic interest shifts (NCT02465060). In pts with PIK3CA mutations, Arm Z1F evaluated copanlisib, a highly selective, pan-Class 1 PI3 K inhibitor with predominant activity against both the δ and alpha isoforms.
Copanlisib (60 mg IV) was administered to Pts in 28-day cycles on days 1, 8, and 15 before progression/toxicity. The tumor evaluation was conducted every 2 cycles. The primary endpoint was objective response rate (ORR); the secondary endpoints were PFS, six-month PFS, and biomarkers for prediction. Pts were omitted for KRAS mutations, HER2+ve breast cancers, and lymphomas.
35 pts have been registered (from 8/2/18 to 12/27/18), of which 28 pts have been available for review (7 patients who are not qualified or who have not begun treatment). Multiple histologies were enrolled with the most common tumors being gynecologic (n = 7), gastrointestinal (n = 6), and genitourinary (n = 5). Median age: 61 years (range 42-78). Seventy-five percent of pts had three previous therapy lines. 54% of mutations in PIK3CA were found in the helical domain, 32% in the kinase domain, and 14% in other domains. Twenty-six pts had gene alterations co-occurring (median 3; range 1-9), with 9 patients having gene alterations of 4 or more. The ORR amounted to 11% (3/28, 90% CI: 3% -25%). Partial responses have been seen in uterine cancer, anterior abdominal wall clear cell carcinoma and liposarcoma. 6 pts had > 6 months of stable disease and 32 percent (9/28) of clinical benefit. Two pts appear to be on medication. Disease progression (n = 18, 69 percent) was the most common explanation for protocol discontinuation. For toxicity analysis, thirty pts were used. Ten pts (33 percent) had toxicity grade 1 or 2; 16 pts (53 percent) had toxicity grade 3; and one patient (3 percent) had toxicity grade 4 (CTCAE v5.0). Hyperglycemia (n=19), fatigue (n=11), hypertension (n=10), diarrhea (n=10), and nausea (n=9) are among the most common toxicities. A total of 5 deaths, none related to treatment, were recorded.
In the late-line refractory environment, copanlisib demonstrated substantial clinical activity across different PIK3CA mutation tumors. Further analysis of selected tumors is warranted either alone or in combinations. The toxicity G3/4 observed was consistent with the toxicity recorded for inhibition of the PI3 K pathway. Details on clinical trials: NCT02465060.