Copanlisib Monotherapy Shows Activity in Uterine Cancers

Patients with deleterious PTEN mutations without PTEN protein loss may benefit from treatment with the pan-PI3K inhibitor copanlisib (Aliqopa). The Z1H arm of the NCI-Match trial (NCT02465060), the largest study of relapsed/refractory solid tumors in the country, was opened to test this hypothesis.

During the study, 35 patients were enrolled and 33 received treatment. Cancers represented included uterine cancer (n = 10), glioblastoma (n = 9), head and neck cancer (n = 4), breast cancer (n = 3), and other cancers (n = 7). At the time of analysis, all patients were off study treatment.

Of the 33 patients who discontinued treatment, 30 discontinued due to disease progression, 1 discontinued due to an adverse event, 1 due to a withdrawal of consent, and 1 patient died. The median progression-free survival was 1.8 months. Twenty-eight patients were evaluated for efficacy and safety.

Filip Janku, MD, PhD, the chief medical officer at Monte Rose Therapeutics and medical oncologist, discussed the efficacy of the PI3K inhibitor copanlisib in solid tumors in an interview with Targeted Oncology™, discussed the efficacy of the PI3K inhibitor copanlisib in solid tumors in an interview with Targeted Oncology™. Janku served as a national principal investigator for the study at the time when he was the Center Medical Director of the Clinical and Translational Research Center and Associate Professor at the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center.

TARGETED ONCOLOGY: Can you give a brief overview of the phase 2 study of PI3K inhibitor copanlisib in cancer patients with deleterious PTEN mutations and retained PTEN protein expression: Results from the NCI-MATCH Trial (EAY131) sub-protocol Z1H?

JANKU: We presented a phase 2 study of copanlisib in patients with advanced cancers whose tumors had deleterious PTEN mutations and retained PTEN protein expression. The study was conducted as a part of the NCI-MATCH trial as subprotocol Z1H. NCI-MATCH is a large national precision oncology trial with more than 1,100 sites involved. The study contains arms with specific targeted therapies for patients whose tumors have matching underlying molecular alterations that are deemed to be associated with sensitivity to these specific treatments.

The concept of the NCI Match trial is the following: patients with previously treated advanced cancers with results of molecular profiling of their tumor tissue, including genomic and protein alterations are eligible to participate. The study aims for each arm to see a greater than 16% response rate based on at least 31 evaluable patients. Secondary objectives include progression-free survival, time to progression, and evaluation of potential predictive biomarkers.

Our arm, Z1H, enrolled patients with any advanced relapsed or refractory solid tumors, lymphoma or myeloma, who met eligibility criteria and had underlying PTEN mutation or deletion with retained PTEN protein expression on immunohistochemistry. The patients must have adequate organ function and good performance status. Patients with other coexisting alterations in the PI3K, mTOR and MAP kinase pathways, that were deemed to be potentially associated with resistance to copanlisib, were excluded.

Copanlisib is a pan-PI3K inhibitor that has been approved for the treatment of relapsed follicular lymphoma and in our study we used the FDA-approved dose of 60 milligrams intravenously on days 1, 8, and 15 of 28-day cycles. The tumor assessment for treatment efficacy was performed every 2 cycles which is a usual standard of care.

Of the 33 patients treated in Z1H arm, 73% were female, 79% were white and 61% of patients had an ECOG score of 1. Our patients were heavily pretreated, with 70% of patients receiving 3 or more prior lines of cancer therapies. Uterine cancer was the most represented tumor type followed by glioblastoma and head and neck cancers.

At a time of analysis, all 33 patients were off study and the most frequent reason for treatment discontinuation was disease progression in 28 of 33. The copanlisib safety profile is well known and adverse events observed in our study fell within what was expected. The most frequent treatment-related adverse event was nausea, which was mostly low-grade, followed by fatigue and hyperglycemia, which is a known on-target effect of many PI3K inhibitors.

The most frequent toxicity among grade 3 or higher adverse events was hypertension, which is again a known side effect of copanlisib. We have also seen few episodes of grade 3 rash, grade 3 fatigue, and grade 3 nausea.

As far as the efficacy is concerned, the study did not meet the efficacy endpoint. However, we have seen one partial response in a patient with uterine cancer, who had a complete resolution of target lesions with persistence of non-target lesions, maintained for 17.4 months.

We also had few patients who did not achieve partial or complete response, but we believe they had some meaningful benefit from therapy such as a patient with squamous non-small cell lung cancer, who experienced tumor shrinkage of 25%, which was maintained for 10.5 months. We've also seen a stable disease for 7 months in a patient with breast cancer, and for 10.7 months in a patient with salivary gland cancer. Otherwise, overall, progression-free survival was only 1.8 months with overall survival of 9 months, which was relatively modest. Overall, in the entire population, copanlisib had rather modest activity in this basket of patients with multiple cancer types with deleterious PTENmutations and retained PTEN protein expression.

However, the deep and durable therapeutic response in 1 out of 10 patients with uterine cancer is noteworthy. The question is, can we identify some additional biomarkers to better select patients who can actually benefit from this treatment?

What is copanlisib mechanism of action?

Copanlisib is an intravenous pan-class I PI3K inhibitor, which has inhibitory effect on PI3K alpha and other subunits.

Did you find anything noteworthy or interesting in your analysis?

Modest activity in overall population was perhaps not that surprising. Quite few studies in solid non-hematological tumors demonstrated that monotherapy with PI3K inhibitors has relatively low efficacy even if molecular selection is utilized. However, a profound and durable response in a patient with uterine cancer was intriguing and it would be worthwhile if we can gain better understanding of underlying biology in these super-responders. In addition, future endeavors should be centered at development of rationale combinations, which can expand the pool of patients with sizable benefit.

What are the future plans of this research?

As far as copanlisib is concerned, there are several ongoing studies testing the drug in combination with other anti-cancer agents. These studies, although not necessarily specific for patients with PTEN alterations, include combinations with immune checkpoint inhibitors, hormone therapy or with other targeted therapies.

I would also like to emphasize that NCI-MATCH program is a truly transforming effort, which generates an unprecedented amount of knowledge that helps to further advance personalized medicine in cancer. In addition, NCI-MATCH program extended access to novel personalized approaches from large cancer centers such as MD Anderson Cancer Center to much smaller community sites. Also, the basket design of NCI-MATCH program allows for efficient and timely go no-go decisions, which are important for future drug development.

^REFERENCE:

^{Janku F, Wei Z, Davies M, et al. Phase II study of PI3K inhibitor copanlisib in cancer patients with deleterious PTEN mutations and retained PTEN protein expression: Results from the NCI-MATCH Trial (EAY131) sub-protocol Z1H. Ann. Oncol. 2021;32(5):5S95 doi:10.1016/j.annonc.2021.08.1052}