Skip to main content
NCBI home page
ESMO Open logoLink to ESMO Open
. 2024 Feb 5;9(2):102217. doi: 10.1016/j.esmoop.2023.102217

Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors

B Perez 1, R Aljumaily 2, TU Marron 3, MR Shafique 1, H Burris 4, WT Iams 5, SJ Chmura 6, JJ Luke 7, W Edenfield 8, D Sohal 9, X Liao 10, C Boesler 11, A Machl 12, J Seebeck 11, A Becker 11, B Guenther 11, A Rodriguez-Gutierrez 13, SJ Antonia 14,∗
PMCID: PMC10937199  PMID: 38320431

Abstract

Introduction

We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors.

Materials and methods

Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B.

Results

In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional.

Conclusions

Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited.

ClinicalTrials.gov Identifier

NCT03724890.

Key words: avelumab, peposertib, phase I, radiotherapy, immunotherapy

Highlights

  • •

    Genomic instability induced by the disruption of DNA damage response pathways can increase sensitivity to immunotherapies.

  • •

    Peposertib, a DNA-dependent protein kinase inhibitor, had preclinical antitumor efficacy in combination with radiotherapy.

  • •

    We assessed the safety and antitumor activity of peposertib + avelumab ± radiotherapy in advanced solid tumors.

  • •

    Peposertib was well tolerated at doses ≤200 mg b.i.d. with avelumab and ≤250 mg q.d. with avelumab + radiotherapy.

  • •

    Peposertib + avelumab ± radiotherapy had limited clinical activity.

Introduction

Targeting DNA damage response (DDR) pathways that are essential for cancer cell survival is a promising therapeutic strategy in oncology.1,2 Combining DNA damage-inducing agents, such as chemotherapy or radiotherapy, with DDR inhibitors can enhance DNA damage, which may increase mutational burden, induce immunogenic cell death, and enhance the release and/or expression of tumor antigens.2 Chemotherapy and radiation cause extensive DNA double-stranded breaks (DSBs), which are particularly lethal for cancer cells.3, 4, 5 DNA DSBs can be repaired by homologous recombination (limited to the S/G2 phases of the cell cycle), which is directed by ataxia telangiectasia mutated kinase, or nonhomologous end joining (NHEJ; active throughout the cell cycle).4, 5, 6 NHEJ is driven by DNA-dependent protein kinase (DNA-PK), and DNA-PK inhibition can exacerbate DNA damage generated by chemotherapy or radiotherapy.7, 8, 9, 10, 11

Although mechanisms by which DDR-inhibiting agents can elicit antitumor immunity have been identified, it is unknown whether DNA repair-directed agents modulate the tumor immune environment or affect sensitivity to immune checkpoint inhibitors (ICIs). Genomic instability induced by the disruption of normal DNA repair pathways may increase tumor mutational burden, formation of neoantigens, and/or stimulator of interferon genes (STING) pathway activation, all of which could increase ICI sensitivity.12,13 Combining DDR inhibition with radiotherapy may increase cytosolic accumulation of double-stranded DNA in tumor cells, which activates the cyclic GMP–AMP synthase/STING-mediated type 1 interferon response in dendritic cells.14 Studies have linked DNA damage or DDR deficiency with antitumor activity of ICIs, and mutations in genes related to DNA damage predict response to ICIs.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 In preclinical studies, combinations of poly(ADP-ribose) polymerase (PARP) inhibitors and ICIs have shown antitumor activity.29, 30, 31, 32 Preliminary efficacy has been observed in studies of PARP inhibitors combined with ICIs in patients with BRCA-mutated breast, ovarian, and prostate tumors.33 Additional clinical studies of ICIs combined with DNA repair-targeting agents are needed.

Peposertib (M3814) is a potent and selective DNA-PK inhibitor that had a well-tolerated safety profile in a first-in-human study.34 In preclinical studies, peposertib in combination with radiotherapy inhibited tumor growth to a greater extent than radiotherapy alone, promoted antitumoral immunity, and increased sensitivity to anti-programmed death-ligand 1 (PD-L1) therapy.11,35, 36, 37 Avelumab is an anti-PD-L1 antibody that has been approved in various countries as first-line monotherapy for metastatic Merkel cell carcinoma, first-line maintenance treatment or second-line treatment for advanced urothelial carcinoma, and first-line treatment for advanced renal cell carcinoma in combination with axitinib.38,39 Here, we report the results of a multicenter, open-label, phase I study that evaluated the safety, tolerability, and pharmacokinetics (PK) of peposertib administered in combinination with avelumab with or without radiotherapy in patients with selected advanced solid tumors.

Materials and methods

Study design and patients

This was a phase I, three-part, multicenter, open-label, dose-escalation study (NCT03724890). Part A assessed escalating doses of peposertib in combination with avelumab. Part B assessed escalating doses of peposertib in combination with avelumab and palliative radiotherapy, and was initiated once the first dosing level of Part A was declared tolerable by the safety monitoring committee (SMC). Part FE assessed the effect of food on the PK of peposertib administered in combination with avelumab under fasted and fed conditions. Only doses of peposertib declared safe and tolerable by the SMC in Part A were investigated in Part FE.

Eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumors for which standard therapy did not exist or had failed, or who were unable to tolerate or had declined established therapy. Additional eligibility criteria and exclusion criteria are summarized in Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2023.102217. In Part B, brain, spinal cord, esophageal, gastric, and primary liver tumors and small bowel lesions were not targeted with radiotherapy.

This trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines, defined by the International Council for Harmonisation. All participating patients provided written informed consent. The protocol was approved by the institutional review board or independent ethics committee at each participating center.

Procedures

Sequential cohorts of patients were enrolled. Avelumab was administered at a dose of 800 mg by 1-h intravenous infusion every 2 weeks (Q2W). Patients received antihistamine and acetaminophen before the first four infusions, and premedication for subsequent doses was based on the frequency and severity of infusion-related reactions (IRRs). Peposertib was administered as 50-mg film-coated hot melt extrudate tablets (estimated 75% increase in bioavailability versus capsules), either twice daily (b.i.d.) continuously in Part A and Part FE or once daily (q.d.) for a total of 10 doses on the same days as radiotherapy in Part B; peposertib was not administered after completion of radiotherapy. Doses of peposertib administered are summarized in Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2023.102217. Radiotherapy (≤3 anatomical sites, irradiated on the same day) was initiated in combination with peposertib on day 1, given as 30 Gy (10 × 3 Gy) per site for 5 days per week. The SMC reviewed safety data for patients enrolled in Part A and Part B and provided recommendations on dose escalation and de-escalation, suspension of enrolment, and declaration of the recommended phase II dose (RP2D) and/or the maximum tolerated dose (MTD).

Patients were treated until disease progression, unacceptable toxicity, or other protocol-specified criteria for withdrawal occurred. Patients who discontinued one study intervention while clinical benefit was ongoing could continue with the other study interventions until protocol-specified criteria for treatment discontinuation were met.

The safety follow-up period was from the date of first study treatment until 30 days after last study treatment, with further safety evaluation carried out 90 days after last dose of avelumab. Part B had additional safety follow-ups to assess the potential toxicity of radiotherapy in combination with peposertib and avelumab, including short-term (30 days), mid-term (3 months), and long-term (12 months) assessments after the end of radiotherapy.

Endpoints and assessments

The primary objective for Part A and Part B was to determine the RP2D and/or MTD of peposertib in combination with avelumab with or without radiotherapy. The primary endpoint for Part A and Part B was occurrence of DLTs from the start of treatment to the planned final assessment (at the end of the DLT period at 3 and 4 weeks, respectively). The primary objective for Part FE was to determine the food effect of the PK of peposertib in combination with avelumab. The primary endpoint for Part FE was the area under the curve (AUC) from time 0 to the last quantifiable sampling time (AUC0-t) and the maximum serum concentration (Cmax) for peposertib. Secondary efficacy endpoints in Part A and Part B included safety, best overall response per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by investigator assessment, and PK.

DLT was defined as any grade ≥3 nonhematologic adverse event (AE) or any grade ≥4 hematologic AE occurring within the DLT evaluation period (21 days for Part A and 28 days for Part B) that was related to any study intervention. Study drug-related treatment-emergent AEs (TEAEs) defined as DLT and exceptions to the definition of DLT are summarized in the Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2023.102217. All DLTs were confirmed by the SMC.

AEs and laboratory abnormalities were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Tumors were assessed using computed tomography and magnetic resonance imaging every 8 weeks for 6 months, then every 12 weeks until progressive disease (PD) per RECIST version 1.1, start of new systemic anticancer therapy, or the end of the study. Irradiated tumor sites were included in analyses of treatment response because radiation was a study intervention. PK and biomarker analyses are summarized in the Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2023.102217.

Statistical analyses

The number of evaluable patients planned for enrolment in the trial was between 18 and 54, dependent on the number of DLTs observed at each dose level and number of tested or expanded dose levels for peposertib. DLTs were assessed in the dose-escalation analysis population, which included patients from Part A and Part B who had completed the DLT period. Additional details are summarized in the Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2023.102217.

The safety analysis population was defined as all patients who received ≥1 dose of study intervention. Best overall response was assessed in the safety analysis population. The PK analysis population included all patients from Part A and Part FE who completed one dose of peposertib and avelumab starting on day 1 and had ≥1 post-dose sample with measurable concentrations of peposertib, and all patients from Part B who completed one dose of peposertib and had PK samples for ≥6 h following first dosing on day 1. Biomarker analyses were conducted using pretreatment archival tumor tissue samples; fresh samples were used in Part A and Part B if archival samples were unavailable. Kaplan–Meier estimates were used for time-to-event analyses, and the Brookmeyer and Crowley method was used to calculate confidence intervals.

Results

Dosing and duration of therapy

Between 27 November 2018 and 13 May 2021, 80 patients were screened at nine centers in the United States, and 57 eligible patients were enrolled across Part A (n = 29), B (n = 19), and FE (n = 9). The data cut-off was 5 August 2022. More than half of the patients were female [32 (56.1%)], and most patients were White [44 (77.2%)] (Table 1). All patients had received prior treatment with ≥1 anticancer drug therapy, with most receiving treatment for metastatic or locally advanced disease. The most common tumor types were colon (22.8%) and rectal (8.8%).

Table 1.

Baseline patient and disease characteristics in Parts A, B, and FE

Part A (n = 29)
 Part B (n = 19)
 Part FE (n = 9)
Peposertib dose 100 mg b.i.d. (n = 4) 200 mg b.i.d. (n = 11) 250 mg b.i.d. (n = 4) 300 mg b.i.d. (n = 6) 400 mg b.i.d. (n = 4) 100 mg q.d. (n = 3) 150 mg q.d. (n = 3) 200 mg q.d. (n = 4) 250 mg q.d. (n = 9) 100 mg b.i.d. (n = 4) 200 mg b.i.d. (n = 5)
Sex, n (%)
 Male 4 (100.0) 5 (45.5) 0 3 (50.0) 1 (25.0) 2 (66.7) 0 2 (50.0) 5 (55.6) 2 (50.0) 1 (20.0)
 Female 0 6 (54.5) 4 (100.0) 3 (50.0) 3 (75.5) 1 (33.3) 3 (100.0) 2 (50.0) 4 (44.4) 2 (50.0) 4 (80.0)
Race, n (%)
 White 3 (75.0) 6 (54.5) 3 (75.0) 6 (100.0) 2 (50.0) 2 (66.7) 3 (100.0) 3 (75.0) 8 (88.9) 4 (100) 4 (80.0)
 Black or African American 1 (25.0) 5 (45.5) 1 (25.0) 0 2 (50.0) 0 0 1 (25.0) 1 (11.1) 0 0
 Asian 0 0 0 0 0 1 (33.3) 0 0 0 0 1 (20.0)
Ethnicity, n (%)
 Hispanic or Latino 0 1 (9.1) 0 0 0 1 (33.3) 0 0 0 0 0
 Not Hispanic or Latino 4 (100.0) 10 (90.9) 4 (100.0) 6 (100.0) 4 (100.0) 2 (66.7) 3 (100.0) 4 (100.0) 8 (88.9) 4 (100) 5 (100)
 Missing 0 0 0 0 0 0 0 0 1 (11.1) 0 0
Age, median (range), years 57.5 (42-80) 53.0 (20-82) 57.0 (28-69) 65.0 (57-67) 56.0 (41-57) 68.0 (39-70) 74.0 (53-79) 61.5 (53-70) 62.0 (44-73) 62.0 (54-76) 73.0 (38-81)
Age, n (%)
 <65 years 2 (50.0) 6 (54.5) 2 (50.0) 2 (33.3) 4 (100.0) 1 (33.3) 1 (33.3) 3 (75.0) 5 (55.6) 3 (75.0) 1 (20.0)
 ≥65 years 2 (50.0) 5 (45.5) 2 (50.0) 4 (66.7) 0 2 (66.7) 2 (66.7) 1 (25.0) 4 (44.4) 1 (25.0) 4 (80.0)
ECOG performance status, n (%)
 0 2 (50.0) 4 (36.4) 3 (75.0) 3 (50.0) 3 (75.0) 2 (66.7) 2 (66.7) 3 (75.0) 4 (44.4) 2 (50.0) 3 (60.0)
 1 2 (50.0) 7 (63.6) 1 (25.0) 3 (50.0) 1 (25.0) 1 (33.3) 1 (33.3) 1 (25.0) 5 (55.6) 2 (50.0) 2 (40.0)
Tumor type, n (%)
 Breast cancer 0 1 (9.1) 0 0 0 0 0 0 0 0 0
 Colon cancer 2 (50.0) 0 1 (25.0) 2 (33.3) 1 (25.0) 1 (33.3) 0 1 (25.0) 3 (33.3) 1 (25.0) 1 (20.0)
 NSCLC 1 (25.0) 1 (9.1) 1 (25.0) 0 0 0 0 0 1 (11.1) 0 0
 Melanoma 0 1 (9.1) 0 0 0 0 0 0 1 (11.1) 1 (25.0) 0
 Small-cell lung cancer 0 0 0 0 1 (25.0) 0 0 0 0 0 0
 Rectal cancer 1 (25.0) 2 (18.2) 0 0 0 0 0 0 1 (11.1) 1 (25.0) 0
 Prostate cancer 0 2 (18.2) 0 1 (16.7) 0 0 0 0 0 0 0
 Bladder cancer 0 0 0 0 0 1 (33.3) 0 0 0 0 0
 Other cancer 0 4 (36.4) 2 (50.0) 3 (50.0) 2 (50.0) 1 (33.3) 3 (100.0) 3 (75.0) 3 (33.3) 1 (25.0) 4 (80.0)
Tumor grade, n (%)
 GX: grade cannot be assessed 0 3 (27.3) 0 0 3 (75.0) 0 2 (66.7) 1 (25.0) 4 (44.4) 0 1 (20.0)
 G1: well differentiated 0 0 0 0 1 (25.0) 1 (33.3) 0 0 0 1 (25.0) 0
 G2: moderately differentiated 3 (75.0) 4 (36.4) 0 2 (33.3) 0 1 (33.3) 1 (33.3) 1 (25.0) 4 (44.4) 1 (25.0) 2 (40.0)
 G3: poorly differentiated 1 (25.0) 3 (27.3) 3 (75.0) 3 (50.0) 0 0 0 2 (50.0) 0 1 (25.0) 2 (40.0)
 G4: undifferentiated 0 0 0 0 0 1 (33.3) 0 0 0 1 (25.0) 0
 Missing 0 1 (9.1) 1 (25.0) 1 (16.7) 0 0 0 0 1 (11.1) 0 0
Time since initial cancer diagnosis, median (range), months 60.3 (30.9-97.4) 44.0 (20.0-186.9) 46.2 (11.1-78.1) 61.1 (39.6-91.9) 34.7 (23.6-89.6) 67.6 (10.7-86.4) 49.6 (40.0-92.8) 49.7 (16.2-174.2) 51.6 (17.0-129.9) 51.4 (42.3-230.8) 21.9 (9.4-49.9)
Time since diagnosis of metastatic disease, median (range), months 35.2 (4.7-69.3) 20.2 (0.8-178.4) 39.1 (5.1-77.9) 47.0 (26.5-90.6) 26.0 (18.2-77.6) 33.4 (10.7-67.5) 19.5 (2.0-41.0) 46.9 (3.9-137.7) 32.1 (2.8-75.6) 28.5 (14.3-44.2) 13.3 (1.6-36.2)
Prior anticancer drug treatment, n (%) 4 (100.0) 11 (100.0) 4 (100.0) 6 (100.0) 4 (100.0) 3 (100.0) 3 (100.0) 4 (100.0) 9 (100.0) 4 (100.0) 5 (100.0)
 ICI 2 (50.0) 2 (18.2) 1 (25.0) 3 (50.0) 0 1 (33.3) 1 (33.3) 3 (75.0) 2 (22.2) 3 (75.0) 0
Prior lines for metastatic or locally advanced disease, n (%)
 1 0 1 (9.1) 1 (25.0) 0 1 (25.0) 0 0 0 1 (11.1) 1 (25.0) 1 (20.0)
 2 2 (50.0) 2 (18.2) 1 (25.0) 0 0 1 (33.3) 1 (33.3) 2 (50.0) 3 (33.3) 2 (50.0) 0
 3 0 2 (18.2) 0 2 (33.3) 2 (50.0) 0 0 1 (25.0) 1 (11.1) 0 2 (40.0)
 ≥4 2 (50.0) 5 (45.5) 2 (50.0) 4 (66.7) 1 (25.0) 2 (66.7) 2 (66.7) 1 (25.0) 4 (44.4) 1 (25.0) 1 (20.0)
Open in a new tab

ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; NSCLC, non-small-cell lung cancer.

In Part A, the peposertib dose was escalated from 100 mg b.i.d. (n = 4) to 200 mg b.i.d. (n = 5), 300 mg b.i.d. (n = 1), and 400 mg b.i.d. (n = 4) (Figure 1A). At the peposertib 200-mg b.i.d. dose level, only one of five patients were assessable for DLT, and treatment was interrupted in other patients due to non-DLT AEs per protocol definition; therefore, the SMC recommended to evaluate ≥1 patient at an additional intermediate 300-mg b.i.d. dose level and escalate to 400 mg b.i.d. if no DLT occurred. No DLT occurred in the first patient who received the 300-mg dose, and thus escalation to 400 mg proceeded. Following DLT at 400 mg b.i.d., the SMC subsequently recommended peposertib de-escalation. Additional patients received peposertib 300 mg b.i.d. (n = 5), then 250 mg b.i.d. (n = 4), and finally 200 mg b.i.d. (n = 6).

Figure 1.

Figure 1

Open in a new tab

DLT profile plots for (A) Part A and (B) Part B. DLT, dose-limiting toxicity.

In Part B, the peposertib dose was escalated from 100 mg q.d. (n = 3) to 150 mg q.d. (n = 3), 200 mg q.d. (n = 4), and 250 mg q.d. (n = 9) (Figure 1B). In total, 19 patients had tumors that were irradiated, with the lung being the most commonly irradiated site (n = 11/19) (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2023.102217). In Part FE, the peposertib dose was escalated from 100 mg b.i.d. (n = 4) to 200 mg b.i.d. (n = 5) (Table 1).

All patients enrolled in Part A, Part B, and Part FE received ≥1 dose of peposertib with avelumab 800 mg Q2W. In Part A, the median duration of therapy was shorter at peposertib dose levels ≥250 mg b.i.d. (2-3 weeks for peposertib and 2-5 weeks for avelumab) versus lower dose levels (8-22 weeks for peposertib and avelumab). In Part B, the median duration of peposertib and radiotherapy was 2 weeks across all dose levels, and the median duration of avelumab therapy was 8-10 weeks across all dose levels. In Part FE, the median duration of therapy with peposertib was higher at the 100-mg b.i.d. dose level versus the 200-mg dose level (19 versus 8 weeks, respectively), while the median duration of therapy with avelumab was similar (9 versus 10 weeks, respectively).

At data cut-off, all patients had discontinued study treatment. Primary reasons for discontinuing all study treatments (in Parts A, B, and FE, respectively) were disease progression [12 (41.4%), 11 (57.9%), 4 (44.4%)], AEs [11 (37.9%), 6 (31.6%), 4 (44.4%)], withdrawal of consent [3 (10.3%), 1 (5.3%), 0], death [1 (3.4%), 0, 0], loss to follow-up [0, 1 (5.3%), 0], and other reasons [2 (6.9%), 0, 1 (11.1%)].

Dose-limiting toxicity

In patients assessable for DLT in Part A, no DLT was observed with peposertib 100 mg (n = 4) and 200 mg (n = 5) b.i.d. (Table 2; Figure 1). At the 400-mg b.i.d. dose level, three of four patients had DLT; one patient had rash (grade 3) and pyrexia (grade 2); one patient had acute kidney injury (grade 3); and one patient had neutropenia (grade 3), neutrophil count decreased (grade 4), and febrile neutropenia (grade 3). After de-escalation to 300 mg and 250 mg b.i.d., one of four and one of two patients, respectively, had a DLT (pneumonitis [grade 3] in both cases). For Part A, the SMC declared peposertib 200 mg b.i.d. plus avelumab 800 mg Q2W as the RP2D/MTD. In Part B, no DLT was reported. Following review of DLT data in Part A and PK profiles, the SMC declared peposertib 250 mg q.d. plus radiotherapy (30 Gy: 3 Gy/fraction × 10 days) plus avelumab 800 mg Q2W as the RP2D/MTD.

Table 2.

DLT in Part A

Peposertib dose 100 mg b.i.d. 200 mg b.i.d. 250 mg b.i.d. 300 mg b.i.d. 400 mg b.i.d.
Patients evaluable for DLT, n 4 5 2 4 4
Patients with DLT, n (%) 0 0 1 (50.0) 1 (25.0) 3 (75.0)
DLTs per patient, n (%)
 1 0 0 1 (50.0) 1 (25.0) 1 (25.0)
 2 0 0 0 0 1 (25.0)
 ≥3 0 0 0 0 1 (25.0)
DLT by preferred term, n (%)
 Febrile neutropenia 0 0 0 0 1 (25.0)
 Neutropenia 0 0 0 0 1 (25.0)
 Pyrexia 0 0 0 0 1 (25.0)
 Neutrophil count decreased 0 0 0 0 1 (25.0)
 Acute kidney injury 0 0 0 0 1 (25.0)
 Pneumonitis 0 0 1 (50.0) 1 (25.0) 0
 Rash 0 0 0 0 1 (25.0)
Open in a new tab

DLT, dose-limiting toxicity.

Safety

In Part A, nearly all patients had ≥1 TEAE, and toxicity increased with peposertib dose escalation (Table 3). No grade ≥3 TEAEs or serious AEs were reported at the peposertib 100-mg b.i.d. dose level. Grade ≥3 TEAEs were reported in seven of 11 patients (63.6%) at the peposertib 200-mg b.i.d. dose level, five of six patients (83.3%) at the 300-mg b.i.d. dose level, and all patients (4/4) at the 250-mg b.i.d. and 400-mg b.i.d. dose levels. The most common TEAEs across all peposertib dose levels were nausea, vomiting, and fatigue (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2023.102217).

Table 3.

TEAEs in Parts A, B, and FE

Part A (n = 29)
100 mg b.i.d. (n = 4)
 200 mg b.i.d. (n = 11)
 250 mg b.i.d. (n = 4)
 300 mg b.i.d. (n = 6)
 400 mg b.i.d. (n = 4)
All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3
TEAE, n (%) 3 (75.0) 0 11 (100.0) 7 (63.6) 4 (100.0) 4 (100.0) 6 (100.0) 5 (83.3) 4 (100.0) 4 (100.0)
 Treatment related 3 (75.0) 0 10 (90.9) 4 (36.4) 3 (75.0) 3 (75.0) 4 (66.7) 2 (33.3) 4 (100.0) 4 (100.0)
 Peposertib related 2 (50.0) 0 10 (90.9) 2 (18.2) 3 (75.0) 2 (50.0) 3 (50.0) 0 4 (100.0) 4 (100.0)
 Avelumab related 2 (50.0) 0 8 (72.7) 3 (27.3) 3 (75.0) 3 (75.0) 3 (50.0) 2 (33.3) 4 (100.0) 4 (100.0)
Immune-related AE, n (%) 0 0 2 (18.2) 2 (18.2) 3 (75.0) 2 (50.0) 2 (33.3) 2 (33.3) 1 (25.0) 1 (25.0)
IRR, n (%) 0 0 3 (27.3) 0 0 0 0 0 0 0
Serious TEAE, n (%) 0 6 (54.5) 4 (100.0) 4 (66.7) 4 (100.0)
 Treatment related 0 3 (27.3) 3 (75.0) 1 (16.7) 3 (75.0)
 Peposertib related 0 0 2 (50.0) 0 3 (75.0)
 Avelumab related 0 3 (27.3) 3 (75.0) 1 (16.7) 3 (75.0)
TEAEs leading to death, n (%) 0 0 0 2 (33.3) 0
 Treatment-related AE leading to death 0 0 0 0 0
Part B (n = 19)
100 mg q.d. (n = 3)
 150 mg q.d. (n = 3)
 200 mg q.d. (n = 4)
 250 mg q.d. (n = 9)
All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3
TEAE, n (%) 3 (100.0) 2 (66.7) 3 (100.0) 2 (66.7) 4 (100.0) 1 (25.0) 9 (100.0) 7 (77.8)
 Treatment related 3 (100.0) 1 (33.3) 3 (100.0) 2 (66.7) 4 (100.0) 0 8 (88.9) 3 (33.3)
 Peposertib related 2 (66.7) 0 1 (33.3) 1 (33.3) 2 (50.0) 0 5 (55.6) 1 (11.1)
 Avelumab related 3 (100.0) 1 (33.3) 3 (100.0) 1 (33.3) 3 (75.0) 0 7 (77.8) 3 (33.3)
 Radiotherapy related 1 (33.3) 0 1 (33.3) 1 (33.3) 3 (75.0) 0 5 (55.6) 1 (11.1)
Immune-related AE, n (%) 0 0 0 0 1 (25.0) 0 2 (22.2) 2 (22.2)
IRR, n (%) 2 (66.7) 0 1 (33.3) 0 2 (50.0) 0 3 (33.3) 1 (11.1)
Serious TEAE, n (%) 2 (66.7) 1 (33.3) 1 (25.0) 6 (66.7)
 Treatment related 1 (33.3) 1 (33.3) 0 2 (22.2)
 Peposertib related 0 0 0 1 (11.1)
 Avelumab related 1 (33.3) 1 (33.3) 0 2 (22.2)
 Radiotherapy related 0 0 0 1 (11.1)
TEAEs leading to death, n (%) 0 0 0 0
 Treatment-related AE leading to death 0 0 0 0
Part FE (n = 9)
100 mg b.i.d. (n = 4)
 200 mg b.i.d. (n = 5)
All grade Grade ≥3 All grade Grade ≥3
TEAE, n (%) 4 (100.0) 3 (75.0) 5 (100.0) 4 (80.0)
 Treatment related 3 (75.0) 1 (25.0) 5 (100.0) 4 (80.0)
 Peposertib related 3 (75.0) 1 (25.0) 5 (100.0) 3 (60.0)
 Avelumab related 3 (75.0) 1 (25.0) 5 (100.0) 3 (60.0)
Immune-related AE, n (%) 0 0 2 (40.0) 2 (40.0)
IRR, n (%) 1 (25.0) 0 1 (20.0) 1 (20.0)
Serious TEAE, n (%) 2 (50.0) 3 (60.0)
 Treatment related 1 (25.0) 2 (40.0)
 Peposertib related 1 (25.0) 1 (20.0)
 Avelumab related 1 (25.0) 2 (40.0)
TEAE leading to death, n (%) 1 (25.0) 1 (20.0)
 Treatment-related AE leading to death 0 0
Open in a new tab

AE, adverse event; IRR, immune-related reaction; TEAE, treatment-emergent AE.

In Part A, serious TEAEs were reported in six of 11 patients (54.5%) at the peposertib 200-mg b.i.d. dose level, four of six patients (66.7%) at the 300-mg b.i.d. dose level, and all patients (4/4) at the 250- and 400-mg b.i.d. dose levels (Table 3). Diarrhea (n = 2; 250 mg b.i.d.) and disease progression (n = 2; 300 mg b.i.d.) were the only serious TEAEs reported in >1 patient across all dose levels. Peposertib-related serious TEAEs occurred in two of four patients (50.0%) at the 250-mg b.i.d. dose level and three of four patients (75.0%) at the 400-mg b.i.d. dose level. At the peposertib 200-, 250-, 300-, and 400-mg b.i.d. dose levels, avelumab-related serious TEAEs occurred in three of 11 (27.3%), three of four (75.0%), one of six (16.7%), and three of four (75.0%) patients, respectively.

The most common peposertib-related TEAEs in Part A were vomiting [9 (31.0%)], nausea [9 (31.0%)], and fatigue [8 (27.6%)], and the most common avelumab-related TEAEs were fatigue [5 (17.2%)], rash [5 (17.2%)], vomiting [4 (13.8%)], and diarrhea [4 (13.8%)]. Peposertib-related pneumonitis occurred in one patient (25.0%) at the peposertib 250-mg b.i.d. dose level, and avelumab-related pneumonitis occurred in one of 11 (9.1%), one of four (25.0%), and one of six (16.7%) patients at the 200-, 250-, and 300-mg b.i.d. dose levels, respectively. TEAEs unrelated to study treatment led to death in two of six patients (33.3%) at the 300-mg b.i.d. dose level.

In Part B, all patients had ≥1 TEAE, and there was no indication of a peposertib dose effect in combination with avelumab and/or radiotherapy on the proportions of patients who had TEAEs, grade ≥3 TEAEs, or serious TEAEs (Table 3). Grade ≥3 TEAEs were reported in two of three patients (66.7%) at the peposertib 100- and 150-mg q.d. dose levels, one of four patients (25.0%) at the 200-mg q.d. dose level, and seven of nine patients (77.8%) at the 250-mg q.d. dose level. The most common TEAEs (reported in ≥2 patients) were nausea, fatigue, and IRR (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2023.102217).

In Part B, serious TEAEs were reported in two of three (66.7%), one of three (33.3%), one of four (25.0%), and six of nine (66.7%) patients at the peposertib 100-, 150-, 200-, and 250-mg q.d. dose levels, respectively (Table 3). Dehydration was the only serious TEAE reported in ≥1 patient across dose levels (250 mg; n = 2/9). Serious TEAEs related to any study treatments occurred in one of three patients (33.3%) at the peposertib 100- and 150-mg q.d. dose levels (both avelumab-related IRRs) and two of nine patients (22.2%) at the 250-mg q.d. dose level (one patient had autoimmune colitis, diarrhea, dehydration, and hyponatremia, related to avelumab; another had hypoxia and pneumonitis, related to peposertib, avelumab, and radiotherapy).

The most common peposertib-related TEAEs in Part B were nausea [n = 5 (26.3%)] and vomiting [n = 3 (15.8%)]. The most common avelumab-related TEAEs were IRR [n = 8 (42.1%)] and fatigue [n = 3 (15.8%)]. The most common radiotherapy-related TEAE was fatigue [n = 3 (15.8%)]. Peposertib-related pneumonitis occurred in one patient (11.1%) at the peposertib 250-mg q.d. dose level, and avelumab-related pneumonitis occurred in one of four patients (25.0%) and one of nine patients (11.1%) at the 200- and 250-mg q.d. dose levels, respectively. No patient had a TEAE that led to death.

In Part FE, all patients had ≥1 TEAE, with no indication of a peposertib dose effect in combination with avelumab on the proportions of patients who had TEAEs, grade ≥3 TEAEs, or serious TEAEs (Table 3). Grade ≥3 TEAEs were reported in three of four patients (75.0%) at the peposertib 100-mg b.i.d. dose level and four of five patients (80.0%) at the 200-mg b.i.d. dose level. The most common TEAEs reported in ≥2 patients in Part FE were fatigue and diarrhea (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.102217).

In Part FE, serious TEAEs occurred in two (50.0%) and three (60.0%) patients at the peposertib 100- and 200-mg b.i.d. dose levels, respectively (Table 3). Sepsis was the only serious TEAE reported in ≥1 patient across dose levels (100 mg; n = 2/4). Peposertib-related serious TEAEs occurred in one patient each at the peposertib 100- and 200-mg b.i.d. dose levels (25.0% and 20.0%, respectively). Avelumab-related serious TEAEs occurred in one (25.0%) and two (40.0%) patients at the peposertib 100- and 200-mg b.i.d. dose levels, respectively.

The most common peposertib-related TEAEs in Part FE were diarrhea [n = 4 (44.4%)] and fatigue [n = 5 (55.6%)], and the most common avelumab-related TEAEs were diarrhea [n = 3 (33.3%)], fatigue [n = 3 (33.3%)], and IRR [n = 2 (40.0%)]. TEAEs unrelated to study treatment led to death in one patient each at the peposertib 100- and 200-mg b.i.d. dose levels (25.0% and 20.0%, respectively).

Antitumor activity

In Parts A and B, no patients had a complete response (CR) or partial response (PR) (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2023.102217). In Part FE, one of nine patients had a PR at the peposertib 200-mg b.i.d. dose level. The responding patient had colon cancer and had received prior adjuvant chemotherapy (folinic acid, fluorouracil, and oxaliplatin); peposertib was discontinued on day 64 following an unspecified grade 2 AE. A best overall response of stable disease (SD) or non-CR/non-PD was reported in five patients (17.2%) in Part A, six (31.6%) in Part B, and three (33.3%) in Part FE, including two patients who were progression free for >12 months (Part A, 100-mg and 200-mg b.i.d. cohorts) and three other patients who were progression free for >6 months (Part A, 100-mg b.i.d. cohort; Part B, 150-mg q.d. cohort; Part FE, 200-mg b.i.d. cohort).

Tumor shrinkage was observed in some patients (Figure 2; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.102217). Reasons for discontinuation in patients who had shrinkage in target lesions without any subsequent increase were as follows: in Part A, four patients (200-, 250-, 300-, and 400-mg b.i.d. dose levels; n = 1 each) discontinued treatment due to AEs (including autoimmune hepatitis with elevated aspartate aminotransferase (AST) and alanine aminotransferase; diarrhea and vomiting; acute kidney injury, mucositis, alkaline phosphatase increased, weakness, and tremors; and febrile neutropenia, absolute neutrophil count decrease, platelet decreased, AST increased, hyponatremia, and pain in extremity). In Part B, two patients discontinued treatment due to pneumonitis (200 mg and 250 mg q.d.; n = 1 each), and one patient discontinued following clinical progression with no further tumor assessment (250 mg). In Part FE, the patient in the 200-mg b.i.d. cohort who had a PR discontinued peposertib due to related AEs (grade 2 rash and arthralgia; grade 1 chills, headache, and pyrexia reported as adverse drug reaction).

Figure 2.

Figure 2

Open in a new tab

Change in tumor size in (A) Part A, (B) Part B,a and (C) Part FE.

aAll lesions, including irradiated lesions, were considered in tumor assessments.

PK analyses

Peposertib exposure was generally proportional to the dose across all dose levels after single or multiple (q.d. and b.i.d.) doses (Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2023.102217). Some accumulation was observed after q.d. and b.i.d. dosing. In Part FE, estimation of exposure after food intake was not possible due to an unexpected delay in the concentration-time profile after food intake (data not shown). While PK analyses suggested that food delayed peposertib Cmax after a single dose, the sampling scheme did not meet or cover tmax and could not provide an adequate estimate of Cmax or AUC.

Biomarker analyses

Biomarker expression was compared in patients with or without disease control (i.e. response or SD). PD-L1 was evaluable in 24 patients in Part A, 16 in Part B, and one in Part FE. In Part A, two of seven patients with PD-L1+ tumors and two of 17 patients with PD-L1− tumors had SD. In Part B, two of seven patients with PD-L1+ tumors and three of nine patients with PD-L1− tumors had SD. In Part FE, the patient who had a PR had a PD-L1− tumor (Supplementary Figure S2A, available at https://doi.org/10.1016/j.esmoop.2023.102217). DNA-PK was evaluable in 26 patients in Part A, 17 in Part B, and one in Part FE. No association between DNA-PK H-score (prevalence/staining intensity) and disease control was observed (Supplementary Figure S2B, available at https://doi.org/10.1016/j.esmoop.2023.102217). MultiOmyx (broad multiplexed immunohistochemistry) analysis of immunologic and proliferation markers in the tumor microenvironment and tumor cell area was carried out in baseline samples from 13 patients in Part B, of whom four had SD. Higher Ki-67 expression in the tumor cell area was observed in three of four patients with disease control (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2023.102217).

Discussion

We report the first clinical study of a DNA-PK inhibitor, peposertib, combined with an ICI, avelumab, with or without radiotherapy. In previous studies, peposertib inhibited DNA-PK in a time- and concentration-dependent manner,34 suggesting that target inhibition would be achieved at the doses examined in this study; however, in this heavily pretreated population with various tumor types, antitumor effects were limited, including only one patient with a PR. The MTD/RP2D for peposertib plus avelumab 800 mg Q2W with or without therapy was 200 mg b.i.d. and 250 mg q.d., respectively.

In Part A, TEAE and DLT profiles showed numerical increases with higher doses of peposertib, particularly 400 mg b.i.d. In Part B and Part FE, TEAE profiles were similar across all doses, with no observable dose effect with peposertib in combination with avelumab with or without radiotherapy. Cases of pneumonitis were reported; however, with consideration of relevant confounders (e.g. lung radiotherapy and disease progression) and the known association with ICIs,40, 41, 42 it was concluded that peposertib did not increase the risk of pneumonitis. No definitive conclusions could be made about exposure parameters because the samples collected did not provide sufficient PK data. Although PK findings in Part FE were inconclusive, a subsequent study in healthy volunteers showed only a mild food effect.43 In biomarker analyses, disease control was not associated with baseline PD-L1 or DNA-PK levels; however, within the few assessable patients in Part B, a potential association between disease control and Ki-67 expression, a proliferation and prognostic marker for multiple cancers, was observed in tumor cells.44

This study had limitations that should be considered when interpreting the results. Small patient numbers within the different dose levels made it difficult to interpret the dose effect of peposertib in combination with avelumab with or without radiotherapy. In addition, the heterogeneity of tumor types may have affected the observed clinical outcomes. Many patients had received prior anticancer drug therapy for advanced disease, including ICIs, and previous studies have shown that heavily pretreated patients may not respond well to ICIs because of immune cell depletion.45,46 Furthermore, patients were not selected for tumors with DDR defects, which have been shown to increase sensitivity to DDR inhibitors in preclinical studies.47, 48, 49, 50, 51, 52 Several clinical studies of peposertib-based combinations are ongoing, including a study of peposertib combined with avelumab and radiation for advanced solid tumors and hepatobiliary malignancies and a study of peposertib combined with radium-223 dichloride with or without avelumab for advanced prostate cancer.53, 54, 55, 56, 57, 58 In addition, trials of DDR inhibitors with different mechanisms of action in combination with ICIs are also in progress.33,59,60

Conclusions

Peposertib was tolerable up to a dose of 200 mg b.i.d. when combined with avelumab and up to a dose of 250 mg q.d. when combined with avelumab and radiotherapy in patients with selected advanced tumors; however, limited antitumor activity was observed.

Acknowledgements

The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers. Medical writing support was provided by Hiba Al-Ashtal of Nucleus Global and was funded by Merck and Pfizer.

Funding

The work was sponsored by Merck [CrossRef Funder ID: 10.13039/100009945] and was previously conducted under an alliance between Merck and Pfizer.

Disclosure

BP has received institutional funding from Bristol Myers Squibb; has served in a consulting or advisory role for AstraZeneca and G1 Therapeutics; and has received honoraria from Daiichi Sankyo. RA has received institutional funding from Merck; has served in a consulting or advisory role for AstraZeneca; has received honoraria from AstraZeneca; and has served in a leadership role for SWOG and NRG (uncompensated). TUM has received institutional funding from Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Merck, and Regeneron; has served in a consulting or advisory role for AbbVie, Arcus, Astellas, Celldex, Genentech, Glenmark, NGM Biopharmaceuticals, Regeneron, and Rockefeller University; and has received travel, accommodations, and expenses from Arcus. MRS has received research funding from Daiichi Sankyo, Jazz Pharmaceuticals, and Pfizer; and has served in a consulting or advisory role for Jazz Pharmaceuticals. HB has received institutional funding from AbbVie, Agios, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, Celgene, CicloMed, Coordination Pharmaceuticals, eFFECTOR Therapeutics, Lilly, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Genentech/Roche, GSK, Gossamer Bio, Harpoon Therapeutics, Jiangsu Hengrui Pharmaceuticals, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicines, Ryvu Therapeutics, Foundation Medicine, Seagen, Tesar, TG Therapeutics, Verastem, Vertex Pharmaceuticals, XBiotech, and Zymeworks; has served in a consulting or advisory role for Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Incyte, Novartis, TG Therapeutics, GRAIL, Roche, and Vincerx Pharma; and holds stock in HCA Healthcare. WTI has served in a consulting or advisory role for Amgen, AstraZeneca, Bristol Myers Squibb, Catalyst, Elevation Oncology, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, G1 Therapeutics, Genentech, Janssen, Jazz Pharmaceuticals, Mirati, NovoCure, Sanofi, and Takeda. SJC has immediate family members employed by Astellas Pharma and Takeda; has received honoraria from RefleXion Medical; has served in a consulting or advisory role for AstraZeneca and Genentech; has received research funding from Merck, Bristol Myers Squibb, and AstraZeneca/MedImmune; and holds patents, royalties, or other intellectual property with UpToDate. JJL has received research funding from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, F-Star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; has served in a consulting or advisory role for 7 Hills, AbbVie, Actym, Alnylam, Alphamab Oncology, Arch Oncology, Atomwise, Bayer, Bright Peak, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Duke Street Bio, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Endeavor, Exo, Flame, F-Star, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Immatics, Immunocore, Incyte, Instil, Inzen, IO Biotech, MacroGenics, Mavupharma, Merck, Mersana, Nektar, NeoTX, Novartis, Onc.AI, OncoNano, Partner, Pfizer, Pioneering Medicines, PsiOxus, Pyxis, Kanaph, RefleXion, Regeneron, Ribon, Roivant, Saros, Servier, Stingthera, STipe, Synlogic, Synthekine, Tempest, and Xilio; holds provisional patents Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); has served in a consulting or advisory role for AbbVie, Evaxion, and Immutep; holds stock or other ownership in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavupharma, NeoTX, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest; and serves in a leadership role for the Society for Immunotherapy of Cancer. DS has received institutional funding from Aadi, Ability Pharma, Amgen, Apexigen, Astellas, AstraZeneca, Bexion, Bristol Myers Squibb, FibroGen, Genentech, Jiangsu Hengrui Pharmaceuticals, Merck, Mirati, NextCure, PanCAN, Regeneron, and Roche; has received speaker fees from Genentech, Incyte, and Seagen; and has received honoraria and served in a consulting or advisory role for Aadi, AstraZeneca, Elevar, Cancer Commons, TransThera, Totus Medicines, and Valar Labs. XL reports employment with Merck Serono Co., Ltd., Beijing, China, an affiliate of Merck KGaA. CB reports employment with Merck. AM reports employment with EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. JS reports employment with Merck and has served in a consulting or advisory role for Merck. AB reports employment with and has served in a consulting or advisory role for Merck. BG reports employment with Merck and holds stock or other ownership in Merck. AR-G reports employment with Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA. SJA reports honoraria from Achilles Biotech, Amgen, AstraZeneca, Caris Life Sciences, Celsius Therapeutics, G1 Therapeutics, GSK, Memgen, Merck, Nektar, Rapt Therapeutics, Venn Therapeutics, Glympse, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and Samyang; has received research funding from Cellular Biomedicine Group; has received nonfinancial support from Amgen; and has served in a consulting or advisory role for Bristol Myers Squibb. WE has declared no conflicts of interest.

Data Sharing

Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck’s (CrossRef Funder ID: 10.13039/100009945) Data Sharing Policy. All requests should be submitted in writing to Merck’s data-sharing portal (https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html). When Merck has a co-research, co-development, or co-marketing or co-promotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.

Supplementary data

Supplementary Materials
mmc1.docx (667.1KB, docx)
Supplementary Table and Figs
mmc2.docx (646.9KB, docx)

References

  • 1.Jackson S.P., Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–1078. doi: 10.1038/nature08467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Brown J.S., Sundar R., Lopez J. Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. Br J Cancer. 2018;118:312–324. doi: 10.1038/bjc.2017.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Jekimovs C., Bolderson E., Suraweera A., Adams M., O’Byrne K.J., Richard D.J. Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising. Front Oncol. 2014;4:86. doi: 10.3389/fonc.2014.00086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chapman J.R., Taylor M.R., Boulton S.J. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47:497–510. doi: 10.1016/j.molcel.2012.07.029. [DOI] [PubMed] [Google Scholar]
  • 5.Trenner A., Sartori A.A. Harnessing DNA double-strand break repair for cancer treatment. Front Oncol. 2019;9:1388. doi: 10.3389/fonc.2019.01388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Blackford A.N., Jackson S.P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801–817. doi: 10.1016/j.molcel.2017.05.015. [DOI] [PubMed] [Google Scholar]
  • 7.Thijssen R., Ter Burg J., Garrick B., et al. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016;128:574–583. doi: 10.1182/blood-2016-02-700328. [DOI] [PubMed] [Google Scholar]
  • 8.Willoughby C.E., Jiang Y., Thomas H.D., et al. Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy. J Clin Invest. 2020;130:258–271. doi: 10.1172/JCI127483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Timme C.R., Rath B.H., O’Neill J.W., et al. The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. Mol Cancer Ther. 2018;17:1207–1216. doi: 10.1158/1535-7163.MCT-17-1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Hafsi H., Dillon M.T., Barker H.E., et al. Combined ATR and DNA-PK inhibition radiosensitizes tumor cells independently of their p53 status. Front Oncol. 2018;8:245. doi: 10.3389/fonc.2018.00245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zenke F.T., Zimmermann A., Sirrenberg C., et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Ther. 2020;19:1091–1101. doi: 10.1158/1535-7163.MCT-19-0734. [DOI] [PubMed] [Google Scholar]
  • 12.McGranahan N., Furness A.J., Rosenthal R., et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–1469. doi: 10.1126/science.aaf1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mouw K.W., Goldberg M.S., Konstantinopoulos P.A., D’Andrea A.D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017;7:675–693. doi: 10.1158/2159-8290.CD-17-0226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Diamond J.M., Vanpouille-Box C., Spada S., et al. Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunol Res. 2018;6:910–920. doi: 10.1158/2326-6066.CIR-17-0581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Le D.T., Uram J.N., Wang H., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Le D.T., Durham J.N., Smith K.N., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Teo M.Y., Bambury R.M., Zabor E.C., et al. DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma. Clin Cancer Res. 2017;23:3610–3618. doi: 10.1158/1078-0432.CCR-16-2520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Teo M.Y., Seier K., Ostrovnaya I., et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol. 2018;36:1685–1694. doi: 10.1200/JCO.2017.75.7740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Hsiehchen D., Hsieh A., Samstein R.M., et al. DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden. Cell Rep Med. 2020;1 doi: 10.1016/j.xcrm.2020.100034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Chen M.H., Pan Y.-R., Wu C.-E., et al. DNA damage and repair gene panel as a biomarker of immune checkpoint inhibitor response. J Clin Oncol. 2020;38 doi: 10.1002/cti2.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Zhou H., Wu L., Yu L., et al. Identify a DNA damage repair gene signature for predicting prognosis and immunotherapy response in cervical squamous cell carcinoma. J Oncol. 2022;2022 doi: 10.1155/2022/8736575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Langer C.J., Gadgeel S.M., Borghaei H., et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497–1508. doi: 10.1016/S1470-2045(16)30498-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Luke J.J., Lemons J.M., Karrison T.G., et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–1618. doi: 10.1200/JCO.2017.76.2229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Karzai F., VanderWeele D., Madan R.A., et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018;6:141. doi: 10.1186/s40425-018-0463-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ott P.A., Bang Y.J., Piha-Paul S.A., et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37:318–327. doi: 10.1200/JCO.2018.78.2276. [DOI] [PubMed] [Google Scholar]
  • 26.Vinayak S., Tolaney S.M., Schwartzberg L., et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5:1132–1140. doi: 10.1001/jamaoncol.2019.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ricciuti B., Recondo G., Spurr L.F., et al. Impact of DNA damage response and repair (DDR) gene mutations on efficacy of PD-(L)1 immune checkpoint inhibition in non-small cell lung Cancer. Clin Cancer Res. 2020;26:4135–4142. doi: 10.1158/1078-0432.CCR-19-3529. [DOI] [PubMed] [Google Scholar]
  • 28.Domchek S.M., Postel-Vinay S., Im S.A., et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21:1155–1164. doi: 10.1016/S1470-2045(20)30324-7. [DOI] [PubMed] [Google Scholar]
  • 29.Higuchi T., Flies D.B., Marjon N.A., et al. CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol Res. 2015;3:1257–1268. doi: 10.1158/2326-6066.CIR-15-0044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Xue C., Xu Y., Ye W., et al. Expression of PD-L1 in ovarian cancer and its synergistic antitumor effect with PARP inhibitor. Gynecol Oncol. 2020;157:222–233. doi: 10.1016/j.ygyno.2019.12.012. [DOI] [PubMed] [Google Scholar]
  • 31.Shen J., Zhao W., Ju Z., et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019;79:311–319. doi: 10.1158/0008-5472.CAN-18-1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Wang Z., Sun K., Xiao Y., et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci Rep. 2019;9:1853. doi: 10.1038/s41598-019-38534-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Vikas P., Borcherding N., Chennamadhavuni A., Garje R. Therapeutic potential of combining PARP inhibitor and immunotherapy in solid tumors. Front Oncol. 2020;10:570. doi: 10.3389/fonc.2020.00570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.van Bussel M.T.J., Awada A., de Jonge M.J.A., et al. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br J Cancer. 2021;124:728–735. doi: 10.1038/s41416-020-01151-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Sun Q., Guo Y., Liu X., et al. Therapeutic implications of p53 status on cancer cell fate following exposure to ionizing radiation and the DNA-PK inhibitor M3814. Mol Cancer Res. 2019;17:2457–2468. doi: 10.1158/1541-7786.MCR-19-0362. [DOI] [PubMed] [Google Scholar]
  • 36.Haines E., Nishida Y., Carr M.I., et al. DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia. Sci Rep. 2021;11 doi: 10.1038/s41598-021-90500-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Wang W., McMillan M.T., Zhao X., et al. DNA-PK inhibition and radiation promote antitumoral immunity through RNA polymerase III in pancreatic cancer. Mol Cancer Res. 2022;20:1137–1150. doi: 10.1158/1541-7786.MCR-21-0725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Bavencio (avelumab). Prescribing Information. EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA; 2023.
  • 39.Bavencio (avelumab). Summary of product characteristics. Merck Europe B.V., Amsterdam, Netherlands, an affiliate of Merck KGaA; 2023.
  • 40.Wang H., Guo X., Zhou J., et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer. 2020;11:191–197. doi: 10.1111/1759-7714.13240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Banavasi H., Kim S., Alkassis S., et al. Immune checkpoint inhibitor-induced pneumonitis: incidence, clinical characteristics, and outcomes. Hematol Oncol Stem Cell Ther. 2021;16:144–150. doi: 10.1016/j.hemonc.2021.09.005. [DOI] [PubMed] [Google Scholar]
  • 42.Zhang A., Yang F., Gao L., Shi X., Yang J. Research progress on radiotherapy combined with immunotherapy for associated pneumonitis during treatment of non-small cell lung cancer. Cancer Manag Res. 2022;14:2469–2483. doi: 10.2147/CMAR.S374648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Becker A., Krebs-Brown A., Vetter C., et al. Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: effect of food and pharmacokinetics of an oral suspension. Clin Transl Sci. 2023;16:2628–2639. doi: 10.1111/cts.13657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Sun X., Kaufman P.D. Ki-67: more than a proliferation marker. Chromosoma. 2018;127:175–186. doi: 10.1007/s00412-018-0659-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Schoenfeld A.J., Hellmann M.D. Acquired resistance to immune checkpoint inhibitors. Cancer Cell. 2020;37:443–455. doi: 10.1016/j.ccell.2020.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Jenkins R.W., Barbie D.A., Flaherty K.T. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118:9–16. doi: 10.1038/bjc.2017.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Riabinska A., Daheim M., Herter-Sprie G.S., et al. Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med. 2013;5 doi: 10.1126/scitranslmed.3005814. [DOI] [PubMed] [Google Scholar]
  • 48.Middleton F.K., Patterson M.J., Elstob C.J., et al. Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition. Oncotarget. 2015;6:32396–32409. doi: 10.18632/oncotarget.6136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Molenaar R.J., Radivoyevitch T., Nagata Y., et al. IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin Cancer Res. 2018;24:1705–1715. doi: 10.1158/1078-0432.CCR-17-2796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Rafiei S., Fitzpatrick K., Liu D., et al. ATM loss confers greater sensitivity to ATR inhibition than PARP inhibition in prostate cancer. Cancer Res. 2020;80:2094–2100. doi: 10.1158/0008-5472.CAN-19-3126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Garbarino J., Eckroate J., Sundaram R.K., et al. Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity. Transl Oncol. 2021;14 doi: 10.1016/j.tranon.2021.101147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Chang A., Liu L., Ashby J.M., et al. Recruitment of KMT2C/MLL3 to DNA damage sites mediates DNA damage responses and regulates PARP inhibitor sensitivity in cancer. Cancer Res. 2021;81:3358–3373. doi: 10.1158/0008-5472.CAN-21-0688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Testing the combination of new anti-cancer drug peposertib with avelumab and radiation therapy for advanced/metastatic solid tumors and hepatobiliary malignancies. ClinicalTrials.gov Identifier: NCT04068194. Last Update: June 30, 2022. https://clinicaltrials.gov/ct2/show/NCT04068194 Available at.
  • 54.Testing the addition of an anti-cancer drug, M3814 (peposertib), to the usual radiation-based treatment (lutetium Lu 177 dotatate) for neuroendocrine tumors. ClinicalTrials.gov Identifier: NCT04750954. Last Update: August 17, 2022. https://clinicaltrials.gov/ct2/show/NCT04750954 Available at.
  • 55.A study combining the peposertib (M3814) pill with standard chemotherapy in patients with ovarian cancer with an expansion in high grade serous ovarian cancer and low grade serous ovarian cancer. ClinicalTrials.gov Identifier: NCT04092270. Last Update: September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04092270 Available at.
  • 56.Testing the addition of M3814 (peposertib) to radiation therapy for patients with advanced head and neck cancer who cannot take cisplatin. ClinicalTrials.gov Identifier: NCT04533750. Last Update: September 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04533750 Available at.
  • 57.Radiation medication (radium-223 dichloride) versus radium-223 dichloride plus radiation enhancing medication (m3814) versus radium-223 dichloride plus m3814 plus avelumab (a type of immunotherapy) for advanced prostate cancer not responsive to hormonal therapy. ClinicalTrials.gov Identifier: NCT04071236. Last Update: March 8, 2023. https://clinicaltrials.gov/ct2/show/NCT04071236 Available at.
  • 58.Testing the addition of a new anti-cancer drug, M3814 (peposertib), to radiation therapy for localized pancreatic cancer. ClinicalTrials.gov Identifier: NCT04172532. Last Update: March 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04172532 Available at.
  • 59.Chan Wah Hak C.M.L., Rullan A., Patin E.C., et al. Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy. Front Oncol. 2022;12 doi: 10.3389/fonc.2022.971959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Shi C., Qin K., Lin A., et al. The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy. J Exp Clin Cancer Res. 2022;41:268. doi: 10.1186/s13046-022-02469-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Materials
mmc1.docx (667.1KB, docx)
Supplementary Table and Figs
mmc2.docx (646.9KB, docx)

RESOURCES