ATR Inhibitors and Paclitaxel in Melanoma

In this issue of Clinical Cancer Research, Kim and colleagues (1) describe a completed phase I study of the ATR inhibitor ceralasertib, in combination with weekly paclitaxel, which demonstrates clinical efficacy in a number of patients, in particular and unexpectedly, in an expansion cohort of patients with melanoma. Despite DNA-damaging agents being the mainstay of cytotoxic chemotherapy for decades, it is only relatively recently that inhibitors of DNA repair have gained traction as cancer therapy. Six years ago, the PARP inhibitor (PARPi) olaparib was the first DDR inhibitor to be approved by the FDA for the treatment of cancer. Since then, four PARP inhibitors have been approved for the treatment of BRCA1 or BRCA2 mutation-related or BRCAness-related breast, ovary, pancreas, and prostate cancer (2). The basis of the sensitivity of this subset of cancers to PARPi is a defect in DNA repair by homologous recombination (HR); PARP inhibition elicits synthetic lethality in this genetic context. Thus, HR provides a specific biomarker to treat with PARPi. Because of the success of PARPi, there has been considerable interest in developing new agents that block additional components of the DDR pathway. Indeed, a number of other inhibitors aimed at multiple DDR targets, such as DNAPK, ATM, CHK1, WEE1 and ATR, have reached the clinic. Among these, ATR has been the subject of particular attention (3). ATR is a serine/threonine–specific protein kinase important for DNA repair, which is activated by DNA damage including replicative stress. Five ATR inhibitors [ATRi; ceralasertib; AZD6738, AstraZeneca); berzosertib (VX-970/M6620, Merck KGA); elimusertib (BAY1895344, Bayer); ART0380 (Artios); and RP-3500 (Repare)] have reached the clinic. The most advanced, ceralasertib, berzosertib, and elimusertib have completed phase I as single agents and have shown some signs of clinical efficacy.

As with PARPi, there have been suggestions that ATRi may have synthetic-lethal interaction partners such as mutations in the ATM or TP53 genes. In addition, it has been proposed that tumor cells undergoing DNA replication stress, which is common in cancer, may be more sensitive to ATRi. However, none of these biomarkers have as yet been fully validated clinically. As well as use as single agents, ATRi have been explored in combination with other therapeutic agents. For example, preclinical studies have demonstrated synergy with DNA-damaging cytotoxic chemotherapy and clinical trials testing these combinations are ongoing. However, combinatorial toxicity has been a challenge.

This new report (1) describes a completed phase I study of ceralasertib, in combination with weekly paclitaxel, which demonstrates clinical efficacy in a number of patients, in particular, in an expansion cohort of patients with melanoma. Paclitaxel, which acts by disrupting microtubules and hence mitosis, was selected a combination of ATRi, in part, because it is a widely used therapy which is standard of care in malignancies such as stomach, lung, breast, and ovarian. Moreover, there have also been suggestions that the ATRi and paclitaxel combination might have a biological rationale as ATR has been described as potentially having a role in ensuring appropriate chromosome segregation in M phase of the cell cycle (Fig. 1).

In the dose escalation phase of the trial, patients were recruited in 7 escalating dose cohorts. This established a recommended phase 2 dose as ceralasertib 240 mg twice a day on days 1–14 plus paclitaxel 80 mg/m² on day 1, 8, and 15, every 28 days. The 14-day drug holiday for ceralasertib was required to allow bone marrow recovery. Common toxicities were blood-related neutropenia, anemia, and thrombocytopenia; nevertheless, this regimen was considered well tolerated. Importantly with these doses and this schedule, ceralasertib could be given at the MTD when used as a monotherapy while being given alongside the approved weekly dose of paclitaxel. This has not been possible with carboplatin where toxicity prevented maximum dosing of ceralasertib.

Fifty-seven patients were treated in total in the various dose cohorts. Initially, the trial was conducted agnostic to cancer site. However, following evidence of durable responses in melanoma patients in cohorts 1–4, cohorts 5 onwards included only patients with metastatic melanoma all of whom had previously been treated with and progressed on an anti–PD-1 or –PD-L1 immunotherapy. Within the 57 patients treated, there was 1 complete response, 12 partial responses, 18 patients with stable disease, 22 with progressive disease, and 4 not evaluable. In those patents with melanoma, the overall response rate was 33% and the disease control rate was 60.6% with median progression-free survival of 3.6 months and median duration of response of 9.9 months. Overall, these observations provide evidence of the clinical activity of the combination of ceratasertib and paclitaxel in malignant melanoma. Of interest was that responses were in cutaneous, acral, and mucosal melanoma after progression on an immune checkpoint inhibitor. Cutaneous melanoma arises in nonglabrous skin, whereas acral melanoma originates in glabrous skin of the palms, soles, and nail beds, and finally mucosal melanoma, the rarest subtype, arises from melanocytes in the mucosal lining of internal tissues (4). Intriguingly, these subtypes of melanoma have somewhat distinct histopathologic and mutational profiles (4).

What were the determinants of response in some patients and why, in particular, were melanomas sensitive? A number of approaches were taken to address this, but the results were inconclusive. Mutational profiling was performed on tumor samples from 48 patients, but there was no significant association between individual gene mutations or mutational signatures and response to therapy. Likewise, levels of expression of ATM, a potential biomarker of response to ATRi, were not associated with response. DDR inhibitors such as PARPi and ATRi have been proposed to enhance immune responses perhaps through induction of STING. An exploratory analysis of PD-L1 was performed on paired biopsies from a single patient with a significant response to ceralasertib measured radiologically. This showed that ATRi treatment in this patient was associated with an increase in PD-L1 expression posttreatment. Target engagement was confirmed as elevated RAD50 phosphorylation (pRAD50), a downstream marker of ceralasertib, was observed. Elevated PD-L1 expression is associated with inflammation and it is therefore possible that the response in this patient is immune related. Although clearly anecdotal, this phenomenon is worthy of study in additional patients. In addition, a phase II study is underway of the combination of ceralasertib and durvalumab (an anti-PD-L1 antibody) in immunotherapy-resistant patients with melanoma. Although immune activation may be responsible for the responses seen, it also seems possible that replicative stress influenced response to the combination of ceralasertib and paclitaxel in this trial. Perhaps of relevance is the previous observation that replicative stress was a hallmark of the response of a subgroup of melanoma cell lines to CHK1 inhibition, a kinase downstream of ATR (5). While the reasons for the responses in this trial are unclear at present, hopefully we will learn more with the analysis of additional samples that will become available as the combination of ATRi and paclitaxel in melanoma is further assessed.

A. Ashworth reports personal fees from GenVivo, GSK, and Genentech; personal fees and other support from Tango Therapeutics, Azkarra Therapeutics, Ovibio Corp, Bluestar, Earli, Ambagon, Phoenix Molecular Designs, Gladiator, Circle, and Cambridge Science Corp; and grants from SPARC and AstraZeneca outside the submitted work; in addition, A. Ashworth holds patents on the use of PARP inhibitors held jointly with AstraZeneca (benefitted financially, and may do so in the future) through the ICR's rewards to inventors scheme. No other disclosures were reported.