Trial results suggest new approaches for difficult-to-treat adult and pediatric cancers
In the final clinical trials plenary session of the AACR Annual Meeting 2023, researchers highlighted promising study results that suggest new approaches for difficult-to-treat adult and pediatric cancers. The session, Novel Biomarker-driven Molecularly Targeted Therapy Trials, was originally presented on Tuesday, April 18, and can be viewed on the virtual meeting platform by registered Annual Meeting participants through July 19, 2023.
Here’s a look at the four trials reported in the session.
Success targeting previously treated solid tumors with activating FGFR1-3 alterations
In the phase II FIGHT-207 trial, the tyrosine kinase inhibitor pemigatinib showed antitumor activity in multiple pretreated solid tumors with fibroblast growth factor receptor (FGFR) alterations, reported Jordi Rodon, MD, PhD, Associate Professor of Investigational Therapeutics at The University of Texas MD Anderson Cancer Center.
Pemigatinib is a selective FGFR1-3 inhibitor approved for cholangiocarcinoma with FGFR2 alterations.
“Pemigatinib showed clinical activity in cholangiocarcinoma, as expected, but also in central nervous system and gynecologic tumors and in pancreatic cancer,” Rodon said. “Responses were detected in patients with FGFR rearrangements and FGFR [single nucleotide variants], including alterations not previously known to be actionable.”
FIGHT-207 used a basket design to explore the safety and efficacy of pemigatinib across multiple tumor types. The basket study design allowed researchers to explore antitumor activity in three patient cohorts with a variety of specific activating FGFR mutations, fusions, and rearrangements.
Cohort A (49 patients) had FGFR fusions/rearrangements. Cohort B (32 patients) had actionable FGFR single-nucleotide variants. Cohort C (26 patients), an exploratory cohort, had FGFR kinase domain mutations and variants of unknown significance. All patients received 13.5 mg of pemigatinib daily in 21-day cycles until disease progression or toxicity.
The overall response rate was 26.5 percent in cohort A, 9.4 percent in cohort B, and 3.8 percent in cohort C. Disease control rate was 65.3 percent in cohort A, 56.3 percent in cohort B, and 34.6 percent in cohort C.
Baseline BPA1 co-alterations were associated with response to pemigatinib, while TP53 co-alterations were associated with poor response. Co-alterations in MAPK and PI3K pathway genes were associated with lack of objective response.
BPA1 was associated with response to pemigatinib, while TP53 co-alterations were associated with poor response. Co-alterations in MAPK and PI3K pathway genes were associated with lack of objective response.
The median age of study participants was 62 years, and just over half of participants were female. The most common cancers were of the breast, bile duct, central nervous system, gynecologic organs, pancreas, and urothelial tract/bladder. Most patients had received two or more previous lines of therapy.
Safety was consistent with earlier reports, Rodon reported.
First-in-human study shows benefits for novel pan-mutant, isoform selective PI3Kα inhibitor
In the ReDiscover trial, RLY-2608 showed encouraging antitumor activity in HR+/HER2 breast cancer with declines in tumor markers and circulating mutant tumor DNA, radiographic tumor reductions, and clinical response with no grade 3 hyperglycemia and manageable adverse events, reported Andreas Varkaris, MD, PhD, Physician Investigator at Massachusetts General Hospital and Instructor in Medicine at Harvard Medical School.
RLY-2608 is the first allosteric, pan-mutant- and isoform-selective PI3Kα inhibitor to be developed. PI3Kα is the most commonly mutated kinase in solid tumors, present in about 30 percent of solid tumors, including 100,000 breast cancers in the United States.
Alpelisib, the only PI3Kα inhibitor approved by the U.S. Food and Drug Administration, is not mutant-selective and disrupts glucose metabolism, resulting in hyperglycemia. Off-mutant, off-target toxicity limits the clinical use of the agent.
ReDiscover explored 12 dose levels of RLY-2608 across a monotherapy arm and an arm of RLY-2608 in combination with fulvestrant. No dose-limiting toxicities have been seen in either arm and the maximum tolerable dose has not been reached, Varkaris said.
There have been no dose interruptions or dose reductions due to hyperglycemia, Varkaris noted, and all grade 1/2 events have been managed with oral hyperglycemic agents.
Of the 16 patients with breast cancer who were treated with RLY-2608 (two patients received monotherapy; 14 received the combination therapy), 56 percent had radiographic tumor reductions.
Patients have remained on treatment for a median of 16 weeks and there have been no discontinuations due to adverse events. Patients in the study had a median age of 63 years, primarily women, and most had received prior lines of therapy.
In addition to tumor reduction in breast cancer, RLY-2608 has shown activity in head and neck, colon, ovarian, prostate, and other cancer, Varkaris said.
Proof of principle for ATRi plus PARPi combination therapy in advanced solid tumors
Combining multiple DNA damage repair (DDR)-targeted agents to enhance antitumor activity is one therapeutic approach under investigation. Poly (ADP-ribose) polymerase inhibitors (PARPi) can be highly effective, but most tumors eventually develop resistance. Adding an ATM and Rad3-related inhibitor (ATRi) could prevent recovery from PARPi-induced DNA damage by inducing rapid, irreversible replication catastrophe and unscheduled mitosis entry, resulting in cell death.
“Camonsertib is a potent, selective oral ATRi with confirmed clinical activity,” said Timothy A. Yap, MD, PhD, Associate Professor in the Department of Investigational Cancer Therapeutics and Medical Director at the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.
Based on preclinical data, the researchers treated patients with relapsed or refractory solid tumors with DDR alterations using intermittent, low-dose camonsertib plus talazoparib, niraparib, or olaparib in two phase I clinical trials, Yap explained. “We saw deep and durable clinical benefit across tumor types regardless of the PARPi partner, and regardless of previous PARPi treatment or the presence of platinum-resistant tumors.”
Across the two trials, TRESR and ATTACC, 43 patients were treated with camonsertib + talazoparib, 29 patients with camonsertib + niraparib, and 35 patients with camonsertib + olaparib. The most common tumor types were ovarian, breast, pancreatic, and prostate, and the most common genetic alterations were in BRCA2, ATM, and BRCA1. Most patients, 67 percent, had received at least three prior treatments.
The most common adverse events among study participants were anemia, neutropenia, and thrombocytopenia. Dose-limiting toxicities were related to myelotoxicity.
The overall clinical benefit rate was 48 percent, Yap reported, ranging from 41 percent with camonsertib + olaparib to 59 percent with camonsertib + niraparib. Molecular response rates ranged from 56 percent for camonsertib + olaparib to 79 percent with camonsertib + niraparib.
Combination PARPi plus ATRi shows promise in advanced pediatric cancers
Arm N of the The European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies, in Relapsed or Refractory Tumors (ESMART) is exploring the combination of olaparib, a PARP inhibitor, and ceralasertib, an ATM inhibitor, in childhood cancers that have advanced molecular profiling available.
“We found that olaparib and ceralasertib are well-tolerated in combination,” said Susanne A. Gatz, MD, Associate Professor of Cancer and Genomic Sciences at the Institute of Cancer and Genomic Sciences, University of Birmingham, U.K. “We have identified preliminary activity in multiple tumors and are recruiting two phase II expansion cohorts.”
Gatz reported results from arm N of the AcSé-ESMART trial, which used a dose-escalation strategy in three age cohorts: 3 to <6 years, 6 to <12 years, and 12 to 18+ years. Gatz described the results from 18 patients with relapsed/refractory solid tumors: eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. All patients had progressive disease and a median of three lines of prior therapy.
The recommended phase II doses were determined to be 150 mg of olaparib daily for 28 days and 80 mg of ceralasertib for the first 14 days for children 12 years and older. Gatz noted that these doses are identical to those used in adults. Dosing for younger children is still being determined.
Most grade 3 or higher adverse events involved blood and lymphatic system disorders, most commonly anemia and decreases in neutrophil or platelet count.
Patients received a median of 3.5 cycles of treatment. There have been two partial responses and nine patients had stable disease, including three with prolonged stable disease.
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