Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. PATIENTS AND METHODS: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

Short course radiotherapy versus radiochemotherapy for locally advanced rectal cancers in the elderly (UNICANCER PRODIGE 42/GERICO 12 study): Quality of life and comprehensive geriatric assessment.

BACKGROUND: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. PATIENTS AND METHODS: In all, 101 patients ≥75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks ± 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. RESULTS: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. CONCLUSION: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged ≥75 treated for locally advanced rectal cancer.

The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers.

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14lowCD16high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

Geriatric Assessment Implementation before Chemotherapy in MEtastatic Prostate Cancer, Results from the Real-Life Study GAMERS.

Geriatric assessment (GA) can predict and improve treatment tolerance and estimate overall survival in older patients with cancer. Several international organizations promote GA; however, data related to its implementation in daily clinical practice are still limited. We aimed to describe GA implementation in patients over 75 years old with metastatic prostate cancer treated with docetaxel as first-line treatment, and with positive G8 screening test or frailty criteria. This retrospective real-world study included 224 patients treated from 2014 to 2021 in four French centers, including 131 patients with a theoretical indication of GA. Among the latter, 51 (38.9%) patients had GA. The main barriers to GA were the lack of systematic screening (32/80, 40.0%), unavailability of geriatric physician (20/80, 25.0%), and absence of referral despite a positive screening test (12/80, 15.0%). With GA performed in only one-third of the patients with a theoretical indication in daily clinical practice, mostly due to an absence of screening test, the use of GA is currently sub-optimal.

Association of chemotherapy and comorbidities with overall survival in elderly patients with early breast cancer: a French population-based propensity score-matched analysis.

BACKGROUND: Additional systemic treatment for early breast cancer in elderly is challenged by increasing comorbidities with age. We aimed to examine the effect of additional chemotherapy on overall survival in patients aged 70 years or older and the impact of comorbidities on chemotherapy benefit. METHODS: This retrospective monocentric cohort study includes data from all patients aged 70 years and older who underwent surgery for an early breast cancer from 1997 to 2016. A propensity score analysis allowed adjustment for chemotherapy prescription preferences based on tumour characteristics. RESULTS: Of 15,599 patients who had surgery for an early breast cancer, 1743 (11.2%) over 70 years old were included, of whom 269 (15.4%) had received additional chemotherapy. Median follow-up was 5.3 years. Multivariate analyses on the propensity-score weighted cohort (n = 1 354) identified improved overall survival in patients with chemotherapy versus without (HR 0.54, 95% CI 0.31-0.92). Chronic obstructive pulmonary disease (HR, 2.16, 95% CI 1.40-3.34) and polypharmacy (HR 1.40, 95%CI 1.07-1.84) were associated with worse overall survival. No statistically significant interactions were identified between these comorbidities and chemotherapy prescription. CONCLUSION: Additional chemotherapy in elderly with early breast cancer is feasible and associated with overall survival benefit, supporting the importance of chemotherapy considerations in this population, and of avoiding undertreatment based on chronological age considerations alone.

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade.

BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

BACKGROUND: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. METHODS: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. RESULTS: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. CONCLUSION: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

Interest and preferences for physical activity programming and counselling among cancer patients aged over 70 years receiving oncological treatments.

OBJECTIVE: The objective of this study is to assess the physical activity interest and preferences of cancer patients aged over 70 years during oncological treatments and to explore how demographic characteristics may modulate preferences. METHODS: From April to May 2018, this cross-sectional study collected data from self-administered questionnaire regarding physical activity interest and preferences in cancer patients receiving oncological treatments in a regional cancer centre. RESULTS: A total of 144 patients completed the questionnaire. Two thirds (n = 95) showed interest in participating in dedicated physical activity programme during oncologic treatments. Patients preferred to exercise in group activities, under the supervision of an exercise instructor, once a week, at a moderate intensity, for 30 min session, in a community fitness centre. Women significantly preferred exercises to improve flexibility (p = 0.03) and to receive counselling in a group (p = 0.03), whereas men preferred to practise strength training (p = 0.02) and to receive counselling with brochures (p = 0.02). As age increases, participants were significantly more inclined to practise physical activity to improve their balance (p = 0.01). CONCLUSION: These preliminary results will facilitate the design of programmes considering current physical activity preferences in older adults with cancer, which could ensure better adherence to physical activity programmes and, in turn, improved health outcomes.

Treatment and outcomes of older versus younger women with HER2-positive metastatic breast cancer in the real-world national ESME database.

BACKGROUND: Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes according to age. METHODS: Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70). RESULTS: Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1-52.4), 35.3 (95% CI, 31.5-37.0) and 54.2 months (95% CI, 50.8-55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3-13.3), 11.1 (95% CI, 10.0-12.3) and 13.2 months (95% CI, 12.7-13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 [95% CI: 2.05-3.79]; endocrine therapy and/or anti-HER2 1.96 [95% CI: 1.43-2.69]). CONCLUSIONS: In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.

A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer.

PURPOSE: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. PATIENTS AND METHODS: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1). RESULTS: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); and arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively. CONCLUSIONS: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.