Peposertib as a radiosensitizing agent in the treatment of locally advanced rectal cancer

Over the years, the management of locally advanced rectal cancer (LARC), defined as clinical stages II and III, has undergone significant evolution. Until recently, the National Comprehensive Cancer Network (NCCN) guidelines recommended preoperative chemoradiation (CRT) followed by adjuvant postoperative chemotherapy for LARC, amidst controversial evidence gathered over the last two decades (1). Notably, two trials, the French EORTC 22921 trial and the Italian I-CNR-RT trial, enrolled patients with LARC who had completed neoadjuvant CRT and surgery. These trials observed that, compared to observation alone, adjuvant chemotherapy was associated with poor tolerability, which led to a lack of improvement in five-year overall survival or distant metastasis rates (2,3). In an attempt to define the optimal perioperative strategy, the practice focus shifted toward a total neoadjuvant therapy (TNT) approach, consisting of neoadjuvant chemotherapy and neoadjuvant CRT (4,5). TNT was shown to improve pathological complete response (pCR) rates at the time of surgery, along with longer progression-free survival, higher rates of chemotherapy completion, reduced time of ileostomy, and improved quality of life (6,7).

Integrating radiosensitizing agents into the preoperative treatment protocol for LARC represents a compelling approach. Ionizing radiation (IR) combined with chemotherapy-based sensitizing agents such as capecitabine or cisplatin is widely used in cancer therapy, exerting its cytotoxic effect by creating double-stranded DNA breaks (DSB) (8). The addition of other DNA-damaging agents to chemotherapy and radiotherapy (RT) may potentiate the effect of IR, which could reduce the need for more invasive and toxic therapies. The DNA-dependent protein kinases (DNA-PK) pathway plays a crucial role in the DNA damage response responsible for repairing DSB, which maintains cell survival (9). Hence, the goal of DNA-PK inhibition is to prevent the repair of double-stranded DNA breaks caused by IR.

Peposertib, a potent, orally available selective inhibitor of DNA-PK, has shown anti-tumor effect in human cervical cancer cell lines by increasing their sensitivity to IR (10). Similarly, in colon, head and neck, lung, and pancreas human xenograft models, peposertib combined with IR led to statistically significant tumor growth inhibition compared to IR alone (10,11). The first-in-human study of peposertib was a phase 1 trial done in patients with different advanced solid tumors (11). The trial showed that peposertib doses of 100–200 mg once daily or 150–400 mg twice daily were well tolerated and had modest efficacy, with 12/31 patients achieving stable disease (11). Additionally, when combined with CRT and cisplatin, peposertib had demonstrated an acceptable safety profile and reasonable response in the treatment of locally advanced head and neck cancer (12). Currently, ongoing trials are investigating its clinical profile in pancreatic adenocarcinoma (NCT04172532), pancreatic neuroendocrine tumors (NCT04750954), glioblastoma (NCT04555577), and hepatobiliary tumors (NCT04068194).

The purpose of the discussed phase 1b trial was to evaluate the safety and efficacy of CRT combined with peposertib in the setting of LARC (13). Herein, 19 patients with LARC were divided into 3 groups comprised of 6 patients each and received peposertib once daily in doses of 100, 150, or 250 mg, with one patient receiving the 50 mg dose, as well as capecitabine 825 mg/m² twice daily and RT for 5 days per week, with a total duration of 5 to 5.5 weeks. The primary endpoint of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose. The trial also included secondary efficacy endpoints of clinical complete response (cCR) and pCR at 8 weeks, as well as safety assessment.

In this trial, peposertib 150 mg daily was identified as the likely highest tolerated dose, with a dose-limiting toxicity (DLT) rate of 16.7% (N=1/6). However, it failed to meet its primary endpoint due to its unfavorable efficacy and safety profiles. Grade ≥3 adverse events occurred in 11/19 patients, and four patients (one in the 150-mg cohort and three in the 250-mg cohort) permanently discontinued peposertib after experiencing GI adverse events, mainly enterocolitis (2/3 of 250 mg), proctitis (1/3 of 250 mg) and diarrhea (150 mg). Additionally, a 1-year safety follow-up showed a high late toxicity rate of 94.7% (N=18/19) across all dose levels, which included gastrointestinal events and prolonged anemia. Furthermore, cCR and pCR were observed at rates of 15.8% [95% confidence interval (CI): 3.4–39.6%; N=3] and 0% (95% CI: 0–17.6%; N=0), respectively.

Although peposertib showed promising preclinical activity, it did not translate into clinical benefits for patients with LARC. The potency of its radiosensitizing properties, which is suggested by the elevated incidence of grade ≥3 adverse events, was not associated with an improved clinical response, as manifested by the low cCR and pCR rates. Although the trial was not powered to elucidate the clinical efficacy of peposertib plus CRT, the observed pCR rate was disproportionately lower than the historical pCR rate of 10% to 25% with neoadjuvant CRT (13). Additionally, the incidence rate of late toxicities in this study significantly exceeds the rates observed in other trials involving neoadjuvant chemoradiotherapy, which range from 0% to 11% (14-23). The low tolerability of peposertib in this trial could be attributed to its combination with RT and full doses of capecitabine (825 mg/m² twice daily), which is already a potent radiosensitizer. These results are comparable to a prior phase 1 trial in locally advanced head and neck squamous cell carcinoma, where peposertib doses of 50 and 100 mg combined with full doses of cisplatin and RT led to significant adverse events, resulting in failure to report an MTD or a recommended phase 2 dose (13). Therefore, the lack of a dose-dependent effect on this excess of late toxicities would restrict the use of peposertib in routine clinical practice. Nevertheless, this study echoes the findings observed in a previous study (13), namely that peposertib acts as a potent radiosensitizer when combined with a DNA-damaging agent and RT, though its effects are limited by a narrow therapeutic index. Therefore, in order to achieve a balance between efficacy and tolerability, future trials should consider further dose adjustments of DNA-damaging agents or explore alternative dosing schedules for radiation therapy.

In summary, this study did not achieve its primary endpoint of determining an MTD while reporting inferior efficacy outcomes compared to historical neoadjuvant CRT regimens. However, this study highlights a novel therapeutic approach for LARC, where the growing emphasis is placed on the optimization of cCR/pCR rates with neoadjuvant therapies, which in turn might allow for organ preservation.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-55/coif). T.B.S. had royalties or licenses in UpToDate; received research funding to institution from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS, consulting fees to institution from Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA and Merck, and consulting fees to individual from Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine and Sanofi. Glaxo SmithKline, Xilio; had license in Imugene, Recursion; and was on the Data Safety Monitoring Board or Advisory Board of the Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan and 1Globe; played leadership or fiduciary role in Imugene, Immuneering, Xilis, Replimune, Artiva and Sun Biopharma. The other authors have no conflicts of interest to declare.

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