FIG S1. TMB distribution in samples from HAWK and CONDOR (A) and EAGLE (B).

FIG S2. Kaplan-Meier plot of OS in the durvalumab monotherapy, durvalumab plus tremelimumab and SoC treatment arms in the NLR ≤ 7 subgroup (A) and NLR > 7 subgroup (B) in EAGLE.

PURPOSE:Understanding the mutational landscape of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is important in identifying biomarkers to determine which patients may benefit from immune checkpoint inhibitors (ICI). EXPERIMENTAL DESIGN:The HAWK (NCT02207530), CONDOR (NCT02319044), and EAGLE (NCT02369874) studies evaluated R/M HNSCC treatment with durvalumab or durvalumab-tremelimumab. Tumor tissue samples pooled from HAWK/CONDOR (n = 153) and plasma cell-free DNA samples from EAGLE (n = 285) were analyzed to identify somatic alterations and association with survival. RESULTS:The mutational landscape was similar in tissue and plasma. Compared with the wild type, TP53 mutations were associated with significantly shorter overall survival (OS; HR; 95% confidence interval) with standard of care (SoC; EAGLE: 2.12; 1.20-3.78) and ICIs (HAWK/CONDOR: 1.49; 1.05-2.12 and EAGLE: 1.44; 0.99-2.10). In EAGLE, patients with TP53 mutations had significantly longer OS with durvalumab-tremelimumab versus SoC (P = 0.045). KMT2D mutations were associated with a trend toward longer OS (HR; 95% confidence interval) versus the wild type in HAWK/CONDOR (0.81; 0.56-1.19) and a trend toward longer OS with ICIs versus SoC in EAGLE. For both mutations, a European Cooperative Oncology Group performance status of 1 was associated with worsened OS, and PD-L1 positivity was associated with improved OS. CONCLUSIONS:This is the first large-scale study to show the mutational landscape of R/M HNSCC and its association with clinical outcomes in patients treated with ICIs or SoC. The TP53 mutation was a negative prognostic marker; however, treatment with durvalumab-tremelimumab significantly improved survival over SoC. Further investigation of KMT2D as a predictive biomarker for immunotherapy in R/M HNSCC is warranted.

AbstractPurpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2− mBC. Patients and Methods: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. Results: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

Supplementary Materials and Methods

Earlier detection of cancer enables intervention when it is more likely to be treatable and curable, resulting in improved patient outcomes, such as the reduction of morbidity and mortality. Analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results data revealed that cancers diagnosed after distant metastasis represent ~18% of all diagnoses and close to half of all deaths.1 Reducing the proportion of cancers diagnosed at late stages is therefore important.

<p>Mutation profiles in ctDNA: truncating and/or pathogenic mutations in DDR or DDR-related pathway</p>

<p>ADA responses</p>

<p>Per-patient ADA responses</p>

Summary of mean (%CV) PK parameters of Total ADC and Active ADC after a single IV infusion of MEDI3726

<p>CTC while on treatment (patients with at least one CTC measurement >50)</p>

<p>CTC while on treatment (patients with at least one CTC measurement >50)</p>

<p>ADA responses</p>

1073 Background: Endocrine therapy is the main treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, many patients experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extra-terminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Pre-clinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy (objective response rate [ORR]) of molibresib combined with fulvestrant in women with HR+/HER2− mBC. The association between early ctDNA dynamics and clinical outcomes was also assessed. Methods: In this phase I/II dose-escalation and expansion study, patients received oral molibresib 60 mg or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− BC with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Baseline and week 4 plasma samples were collected and tested using a 74-gene ctDNA panel. Molecular response (MR) was defined as at least 50% reduction of baseline ctDNA level calculated as the average allele frequency of detected single nucleotide variants or indels. Results: The study included 123 patients. The 3 most common molibresib-related adverse events (AEs) were nausea (52%), dysgeusia (49%), and fatigue (44%). At molibresib 60 mg, >90% patients experienced treatment-related AEs, with varying incidence of Grade ≥3 AEs (17%–71%) amongst subgroups. The ORR was 13% (95% confidence interval [CI], 8–20), not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected baseline circulating tumor DNA, a strong association was observed between baseline copy number amplification (CNA) presence and poor progression-free survival (PFS) with hazard ratio (HR) of 2.89 (95% CI, 1.73–4.83; P < 0.0001). MR was significantly correlated with better PFS (HR=0.38; 95% CI, 0.19–0.75; P = 0.0037), which was further improved when MR was refined as no baseline CNA (HR=0.22; 95% CI, 0.09–0.54; P = 0.0003). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Copy number adjusted ctDNA MR is a promising early marker for clinical benefit. Clinical trial information: NCT02964507 .

<p>Per-patient ADA responses</p>

Background: Previous studies have shown that ctDNA MR defined by 50% reduction of ctDNA levels after immune checkpoint inhibitor (ICI) treatment is significantly associated with improved survival. However, discordance between MR and radiologic response was observed, hindering the potential use of MR as a surrogate endpoint. We report a meta-analysis of MR rate (MRR) and radiologic objective response rate (ORR) with ICI intervention. The relationship between MRR difference and hazard ratio of survival has also been assessed using two independent approaches. Methods: MRR, ORR and overall survival (OS) data were compiled from 9 study arms where metastatic solid tumors were treated by ICI. Weighted least squares linear regression method was used to study the relationship between MRR and ORR. Patient level MR and OS data were downloaded from the original report (Set 1) or by digitizing Kaplan-Meier plot using Guyot algorithm (Set 2). The correlation of MRR difference between two arms and hazard ratio for OS was assessed using samples generated by bootstrapping with replacement. Similarly, a parametric simulation by fitting a piecewise exponential curve was also performed to confirm the above finding. Results: A total of 958 patients were eligible for this analysis. A significant correlation between MRR and ORR was identified across 9 study arms after adjusting sample size (Adjusted R2=0.91, P<0.0001). Under a hypothetical scenario of two randomized study arms, an inverse correlation between MRR difference and hazard ratio was observed using both bootstrapping and parametric simulation approaches across different conditions. A stronger negative trend was found in Set 1 compared with Set 2, where MR showed a better association with OS in the former (HR=0.27 versus HR=0.41) Conclusions: This meta-analysis showed for the first time that ctDNA molecular response rate may be a surrogate for radiologic objective response rate in ICI and could enable early decision making. Since most of the data analyzed here is from patients with non-small cell lung cancer, the extrapolation of these findings to other tumor types needs further validation. Citation Format: Qu Zhang, Andy Houseman, Sammy Yuan, Joe Harding, Helen Zhou, Bin Feng, Michael L. Washburn. Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1041.