Preliminary trial results demonstrate benefit of FGFR and PARP/ATR inhibitors

ABSTRACT: CT016, CT018

ORLANDO, Florida ― Researcher from University of Texas MD Anderson Cancer Center presented promising findings from several clinical trials today in American Association for Cancer Research (AACR) Annual Meeting 2023. The studies, which describe the results of the new FGFR inhibitors and of the new PARP/ATR inhibitor combinations, were presented in a plenary session highlighting new molecularly driven biomarkers. targeted therapy test. Information on all of the MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR.

The results of the basket trial suggest a wider population may benefit from the FGFR inhibitor pemigatinib (Abstract CT016)

FIGHT-207 trials, led by Jordi Rodon, MD, Ph.D., associate professor of Investigative Cancer Therapydemonstrated promising early signs of clinical benefit and uncovered potential mechanisms of primary and secondary resistance following treatment with the selective FGFR inhibitor pemigatinib in patients with advanced disease FGFR-transforming solid tumors.

Pemigatinib achieved response across a wide variety of tumor types, with the highest objective response rate (26.5%) in a cohort of patients with FGFR1-3 fusion. This includes responses in glioblastoma And pancreas cancer, which is not known to respond to FGFR inhibitors, and patients not previously reported FGFR change.

The researchers also found that the mutations that occurred together correlated with the patient’s response. For example, BAP1 mutations were associated with higher response rates, transient TP53 change is associated with lower response rates.

“This study highlights the value of basket trials as a discovery tool. Instead of segmenting by type of cancer, this trial is segmenting cohorts by type of mutation,” said Rodon. “There are still a lot of unknowns with FGFR inhibitors, with FGFR mutations that promote sensitivity and resistance, and with tumor types where these changes promote growth. This basket trial allowed us to explore these unknowns from a mutational rather than a histological point of view to see what types of patients might benefit.

FGFR changes promote cancer development in various types of tumors, making them promising targets for therapy. However, the lack of target selectivity for first-generation FGFR inhibitors often results in intolerable toxicity, limiting their effectiveness in the clinic. Pemigatinib overcomes this by selectively targeting certain FGFR proteins commonly found in cancer; it was previously approved by the Food and Drug Administration (FDA) for use in refractory cholangiocarcinoma and myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

The open-label, single-armed Phase II basket study was designed to evaluate the efficacy and safety of pemigatinib in patients with previously treated unresectable or metastatic solid tumors. FGFR mutation or fusion/rearrangement. The trial enrolled 111 patients and grouped the participants into three cohorts based on their specific type FGFR change. Patients were 56% female with a mean age of 62 years; 56% had more than two previous courses of therapy.

Safety is consistent with previous pemigatinib studies, with the most common side effect being hyperphosphataemia, or excess phosphorus in the blood, in 84% of patients, followed by stomatitis (53.2%), alopecia (41%), diarrhea (39%). and constipation (33%) Of these, only stomatitis (9%) occurred at grade 3 or higher in more than 1% of patients.

This trial is powered by Incyte. A full list of authors and their disclosures can be found Here.

PARP and ATR inhibitors in combination show promising initial results (Abstract CT018)

Two trials led by Timothy A. Yap MD, Ph.D., associate professor of Investigational Cancer Therapeutics, showed encouraging results for treating solid tumors with altered DNA damage response using a combination of PARP and ATR inhibitors. Notably, anti-tumor activity was seen in patients with tumors that had previously shown resistance to PARP inhibitors or platinum-based therapy.

The researchers studied the combination of the ATR inhibitor camonsertib with each of the three currently approved PARP inhibitors, niraparib, talazoparib and olaparib. The clinical benefit rate (CBR) for all patients in this heavily treated population was 48%, with an overall response rate (ORR) of 18% in the nonaparib group and 10% in the talazoparib and olaparib treated groups, respectively. The high molecular response rate using circulating tumor DNA further confirms the treatment effect and offers a mechanistic explanation for the lasting clinical benefit.

The highest response rates were seen in patients with ovarian cancer. Among the 19 patients, the ORR was 32% and the CBR was 58%, with a median progression-free survival of about seven months and at least 16 weeks of treatment lasting in nine patients.

“We really need a better approach with PARP inhibitors to maximize the benefits, and the combination of pre-clinical data support with ATR inhibitors. This study was designed to evaluate the optimal combination from the point of view of tolerability and toxicity,” said Yap.

PARP inhibitors have been approved for certain types of cancer since 2014, but not all patients respond and those that do often develop resistance, limiting their clinical effectiveness. To overcome this problem, researchers studied the effectiveness of combining it with an ATR inhibitor.

ATR inhibitors are similar to PARP inhibitors in that they target DNA damage repair pathways. In cells with defects in the repair pathway, this leads to an accumulation of cell damage and eventual cell death. Pre-clinical studies show that, because the two work toward the same goal using different mechanisms, their combination makes them more effective than either alone.

The two Phase I/II trials included a total of 107 patients, with 90 patients subject to evaluation for efficacy at the time the AACR data was truncated. Patients received an average of three previous lines of therapy, including 39% of patients previously treated with PARP inhibitors and 78% of patients who were platinum resistant or refractory.

The challenge in bringing this combination to the clinic is overcoming the overlapping toxicity associated with the two inhibitors. In this trial, both drugs were administered at low intermittent doses based on strong pre-clinical modeling data supporting this new approach.

“Using this dosing technique, we were able to obtain the efficacy of the combination without severe toxicity,” said Yap. “We were very pleased to see the response even in patients who had previously been treated with PARP inhibitors and were resistant to them, which is a critical area of ​​unmet need that is urgently needed in the clinic.”

In general, the combination was well tolerated. The most common adverse events were short-term reversible haematological adverse events, such as anemia, without growth factor prophylaxis required in this study. Dose optimization in a molecularly driven tumor-specific expansion cohort is ongoing.

This trial is supported by Repare Therapeutics through a strategic partnership with MD Anderson. A full list of collaborating authors and their disclosures can be found here.