In three new clinical trials, researchers have found that the novel fibroblast growth factor receptor (FGFR) inhibitor pemigatinib and new poly (ADP ribose) polymerase (PARP)/ataxia telangiectasia and Rad3-related (ATR) inhibitor combinations may be effective at treating patients with multiple tumor types, according to new findings presented by Rodon et al (Abstract CT016) and presented by Yap et al (CT018) at the American Association for Cancer Research (AACR) Annual Meeting 2023.
Background
FGFR mutations may drive cancer progression in multiple tumor types, making them a promising target for therapies. However, a lack of target selectivity in first-generation FGFR inhibitors has frequently led to toxicities and limited their clinical effectiveness. Pemigatinib—previously approved by the U.S. Food and Drug Administration for patients who had refractory cholangiocarcinoma and myeloid/lymphoid neoplasms with FGFR1 rearrangement—has shown promise at overcoming these barriers by selectively targeting certain FGFR proteins commonly found in cancers.
PARP inhibitors have been approved for certain cancer types since 2014, but not all patients respond to treatment—and those who do often build up resistance, limiting the clinical effectiveness of the drugs. To overcome these problems, researchers from the second study analyzed the effectiveness of combining them with an ATR inhibitor.
ATR inhibitors—similar to PARP inhibitors—are designed to target the DNA damage-repair pathway. Cells with defects in repair pathways may experience a buildup of cell damage, which ultimately leads to cell death. Preclinical studies suggest that, since PARP and ATR inhibitors work toward the same goal using different mechanisms, the combination therapy might make them more effective than monotherapy.
Researchers Suggest Wider Population May Benefit From Pemigatinib
In the new open-label, single-arm phase II FIGHT-207 trial, researchers evaluated the safety and efficacy of pemigatinib in 111 patients with a median age of 62 years who had previously treated, unresectable or metastatic solid tumors harboring FGFR mutations or fusions/rearrangements. The trial participants were grouped into three cohorts based on their specific type of FGFR mutation. The researchers reported that 56% of the patients were female and 56% of them had received more than two prior lines of therapy.
FIGHT-207 demonstrated promising early signs of clinical benefit and unveiled potential mechanisms of primary and secondary resistance following treatment with pemigatinib in this patient population. Pemigatinib achieved responses across multiple tumor types, with the highest objective response rate of 26.5% in the cohort containing patients with FGFR1 through FGFR3 fusions. These include responses in patients with glioblastoma and pancreatic cancers—who were not previously known to respond to FGFR inhibitors—and those with previously unreported FGFR mutations.
The researchers also found that certain co-occurring mutations correlated with patient responses. For example, BAP1 mutations were associated with higher response rates, while TP53 mutations were associated with lower response rates.
The researchers reported that pemigatinib’s safety profile was consistent with previous studies of the drug—and noted that the most common adverse events were hyperphosphatemia in 84% of the patients, stomatitis in 53.2% of the patients, alopecia in 41%, diarrhea in 39%, and constipation in 33%. Among these side effects, only 9% of stomatitis cases occurred at a grade 3 level or higher in more than 1% of patients.
“This study highlights the value of basket trials as a discovery tool. Instead of grouping by cancer type, this trial grouped cohorts based on types of mutations,” explained lead study author Jordi Rodon, MD, PhD, Associate Professor of Investigational Cancer Therapeutics in the Division of Cancer Medicine and Medical Director of the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center.
Promising Early Results With Combination PARP/ATR Inhibitors
In two new phase I/II trials, the researchers assigned 107 patients who had solid tumors with DNA damage response mutations—90 of whom were evaluable for efficacy at the time of the AACR data cutoff—to receive a combination of the ATR inhibitor camonsertib with each of three currently approved PARP inhibitors: niraparib, talazoparib, and olaparib. The patients involved in the studies had received a median of three prior lines of therapy—including PARP inhibitors in 39% of patients—and 78% of the patients had platinum-resistant or refractory solid tumors.
The researchers demonstrated encouraging results and, most notably, antitumor activity was seen in patients with tumors that had previously shown resistance to PARP inhibitors or platinum-based therapies.
The clinical benefit rate for all of the patients from both studies was 48%, with an overall response rate of 18% in the niraparib group and 10% in each of the groups treated with talazoparib and olaparib. The high molecular response rate using circulating tumor DNA further showed potential effectiveness and offered a mechanistic explanation for the durable clinical benefit.
The highest response rates were seen in patients with ovarian cancer. Among these 19 patients, the clinical benefit rate was 58% and the overall response rate was 32%, with a median progression-free survival of about 7 months and treatment of at least 16 weeks ongoing in nine patients.
“We really need better approaches with PARP inhibitors to maximize their benefit, and preclinical data support combinations with ATR inhibitors. This study was designed to evaluate the optimal combination from a tolerability and toxicity standpoint,” emphasized lead study author Timothy A. Yap, MD, MBBS, PhD, FRCP, Associate Professor of Investigational Cancer Therapeutics as well as Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine, Medical Director of the Institute for Applied Cancer Science, and Associate Director of Translational Research at the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center.
In general, the combination of PARP and ATR inhibitors was well tolerated. The most common adverse events were short-term reversible hematologic side effects such as anemia, with no prophylactic growth factors required in the study. The researchers indicated that dose optimization in molecularly driven, tumor-specific expansion cohorts is currently ongoing.
Conclusions
“There remain a lot of unknowns with FGFR inhibitors, with FGFR mutations that drive sensitivity and resistance, and with tumor types where these [mutations] drive growth. The [FIGHT-207] trial allowed us to explore these unknowns from a mutational rather than a histologic point of view to see what other types of patients may benefit,” Dr. Rodon highlighted.
Researchers from the second study noted that the challenge in bringing PARP- and ATR-inhibitor combinations to the clinic has been overcoming the overlapping toxicities associated with both drug types. Both agents were given at low intermittent doses based on strong preclinical modeling data supporting this novel approach.
“Using this dosing technique, we were able to get combinatorial efficacy without the severe toxicity,” Dr. Yap stressed. “We were very excited to see responses even in patients who previously had been treated with a PARP inhibitor and were resistant to it, which is a critical area of unmet need that is urgently required in the clinic,” he concluded.
Disclosure: The research in the FIGHT-207 trial was supported by Incyte. The research from the second study was supported by Repare Therapeutics through a strategic collaboration with The University of Texas MD Anderson Cancer Center. For full disclosures of the study authors, visit abstractsonline.com and abstractsonline.com.
