Combination therapy shows preliminary antitumor activity in pediatric neuroblastoma
Key findings:
- Three of four patients with neuroblastoma had stable disease through four or more treatment cycles.
- Phase 2 is ongoing, with the recommended dose yet to be established for patients aged 11 years and younger.
The combination of olaparib and the investigational ATR inhibitor ceralasertib induced antitumor responses in children and adolescents with DNA repair-deficient tumors, according to phase 1 results of the AcSé-ESMART trial.
The data, presented at American Association for Cancer Research Annual Meeting, also showed ceralasertib (AZD6738, AstraZeneca) plus olaparib (Lynparza, AstraZeneca) — a poly(ADP-ribose) polymerase (PARP) inhibitor — to be well tolerated, with a manageable safety profile.
“Preliminary responses show this could be a good strategy to move forward,” Susanne Gatz, MD, PhD, associate clinical professor in pediatric oncology at University of Birmingham’s Institute of Cancer and Genomic Sciences in the United Kingdom, said during a presentation. “Patients with neuroblastoma may benefit from this approach.”
Background
Many malignancies in younger patients exhibit a constitutively active ATR pathway due to endogenous replication/transcription stress that can be targeted by ATR inhibitors, according to researchers.
“Classical BRCA alterations are rare and alterations conferring homologous recombination deficiency (HRD) likely require a combination approach, including PARP inhibitors,” they wrote.
PARP inhibitors are mainly used in adults with BRCA deficiency, and the ATR inhibitor is then used to overcome resistance to the PARP inhibitor, Gatz said.
“The alterations we see in pediatric cancer are different, but may lead to the same result,” she added. “We look at this approach as a potentially reverse situation, where patients have primary resistance to PARP inhibitors and the ATR inhibitor’s blockage of this overactive pathway then helps to sensitize them to the PARP inhibitor.”
Methodology
The Europe-based AcSé-ESMART trial, an international phase 1/phase 2 proof-of-concept study, aimed to match younger patients with relapsed or refractory malignancies with treatment regimens targeted to their tumor’s molecular profile.
Arm N of the trial is designed to match patients with malignancies harboring alterations that cause defects in DNA replication and damage repair to treatment with the combination of olaparib plus ceralasertib.
AcSé-ESMART included 18 children and young adults (median age, 16.5 years; range, 4-24; 55.5% males) with relapsed or refractory malignancies whose tumors — via advanced molecular profiling — had evidence of alterations promoting HRD or replication stress.
Eight participants had sarcoma, five had central nervous system tumors, four had neuroblastoma and one had carcinoma. Sixteen patients (89%) had metastatic disease.
Study participants received oral olaparib twice daily and oral ceralasertib twice daily on days 1 through 14 of a 28-day treatment cycle. Patients received a median 3.5 cycles of treatment (range, 1-12) at one of three dose levels depending on age:
- 12-18 years: olaparib 150 mg twice daily, ceralasertib 80 mg twice daily
- 6-11 years: olaparib 100 mg twice daily, ceralasertib 40 mg twice daily
- 3-5 years: olaparib 50 mg twice daily, ceralasertib 30 mg twice daily
The study’s dose-escalation portion followed a Bayesian optimal interval design that included two expansion cohorts. One cohort comprised patients with homologous recombination-deficient tumors, whereas the other included those whose tumors harbored replication-stress amplifications.
Twelve participants received treatment at the recommended phase 2 dose after concluding the phase 1 portion of the study.
Establishing the recommended phase 2 dose served as the primary objective of the phase 1 portion of the study, and assessing preliminary antitumor activity in molecularly enriched patient cohorts served as the phase 2 primary objective. Secondary objectives included establishing a treatment-related toxicity profile and pharmacokinetics.
March 24 served as the data cutoff date.
Key findings
Researchers found the regimen to be well tolerated but noted some hematologic and gastrointestinal treatment-related toxicities. The most frequently reported included thrombocytopenia, neutropenia, anemia and nausea/vomiting.
Five patients experienced dose-limiting toxicity, including grade 3 or grade 4 thrombocytopenia lasting more than 7 days in each patient.
Grade 4 neutropenia lasting more than 7 days occurred in all three patients treated at dose level 2, leading the investigators to establish olaparib 150 mg twice daily on days 1 to 28 and ceralasertib 80 mg twice daily on days 1 to 14 as the recommended phase 2 dose for patients aged 12 to 18 years.
A recommended phase 2 dose for patients aged 11 years and younger has not yet been determined.
Investigators reported two partial responses, including one patient with pineoblastoma who started responding after three cycles of treatment and another with neuroblastoma who started responding to therapy after cycle nine.
Nine patients had stable disease as their best response to therapy, including three patients (two with neuroblastoma and one with a papillary spinal cord tumor) with prolonged stable disease lasting more than four cycles of treatment.
Clinical implications
Further study via gene- and protein-level analysis is needed to uncover “specific biomarker constellations” in younger patients who receive the combination of olaparib and ceralasertib, Gatz said.
“It will be important to get the first pharmacokinetic data back soon for the explored dose levels, as this will help us to better guide dosing and development in younger children,” she told Healio.
When asked whether this combination therapy has a role in treating younger patients with DNA repair-deficient tumors, Gatz said the regimen has shown clinical benefit across tumor types. “However, neuroblastoma stands out as having the most notable responses based on the results thus far,” she said. “Retrospective molecular in-depth correlative analyses will be key to identifying new hypotheses for patient selection and potential biomarkers for response.”
Perspective
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This is an important study as it demonstrates the safety and tolerability of a novel molecularly targeted combinatorial approach in the pediatric population. In addition, early signals of antitumor activity are observed in biomarker-selected pediatric patients, highlighting the importance of a molecularly driven approach in pediatric oncology.
The underlying mechanism of action of this PARP inhibitor and ATR inhibitor combination is likely multifactorial, including the overreliance on different DNA damage response pathways in cancer cells, as well as catastrophic replication stress. Although the first clinical data for this combination of ceralasertib and olaparib in adults were presented in 2016, it is gratifying to see these early but promising data in the pediatric population.
In terms of what we can learn from adult clinical trials of similar PARP inhibitor/ATR inhibitor combinations, safety and tolerability — as well as molecularly driven patient selection using predictive biomarkers of response — will be important in the future development of this combination. Creative dosing schedules — for example, low-dose intermittent concomitant dosing of both drugs or sequential dosing of both drugs — are also being explored in adult clinical trials to optimize the therapeutic window of this combination.
Prospective molecular testing of patients for both germline and somatic mutations associated with sensitivity to this combination will also be key to success. I look forward to seeing more safety and efficacy data of this combination in a larger population of pediatric patients in the near future.
Reference:
Yap TA, et al. Eur J Cancer. 2016;doi:10.1016/S0959-8049(16)32607-7.
Perspective
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PARP inhibitors were the first DNA damage repair (DDR) small molecule inhibitors the FDA approved to treat several adult solid tumors, but no PARP inhibitors have been approved to treat children with cancer. The mechanism for their antitumor activity is synthetic lethality with BRCA1/BRCA2 mutations, termed “BRCAness.” This refers to a deficiency in a type of DNA repair called homologous replication.
This study highlights the promise of targeting the DNA damage repair pathway in children with solid tumors.
Gatz and colleagues report their observations of a phase 1 trial of olaparib in combination with ceralasertib in children with recurrent solid tumors whose tumors had some signal of homologous replication deficiency or replication stress. The investigators should be congratulated for moving forward with this combination before studies with ceralasertib monotherapy have been completed in the pediatric population.
The trend to move toward drug combinations early in clinical development is likely to accelerate progress in pediatric oncology. The downside is the interpretation of responses in a small population of patients with diverse histology. Assessment of target engagement in the tumor cells of patients in the study can be helpful with interpretation of the results. For example, is the response in the patient with pineoblastoma due to the PARP inhibitor, the ATR inhibitor or both drugs in combination? This is particularly important for CNS tumors due to the challenges of drug delivery across the blood-brain barrier.
Additional research should focus on identifying biomarkers for response that can guide further clinical development of this combination. Examples of biomarkers to explore include alternative lengthening of telomeres and immune activation such as PD-L1 expression, the presence of CD8 T cells in the tumor and tumor mutational burden. Results of the biomarker analysis can inform whether to combine with cytotoxic agents and/or immune checkpoint blockade.
Icahn School of Medicine at Mount Sinai
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Gatz SA, et al. Abstract CT019. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.