Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations.

BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity.

Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICI), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, that could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives.

PURPOSE: HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. METHODS: This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches. RESULTS: 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines. CONCLUSIONS: ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

Comparison of tumor microenvironment in primary and paired metastatic ER+/HER2- breast cancers: results of a pilot study.

BACKGROUND: Tumor microenvironment (TME) is a dynamic setting and changes in TILs and their subpopulations are potential candidates to influence the metastatic process. Aim of this pilot study is to describe the changes occurring between primary breast cancers and their paired metastases in terms of TILs composition. To assess if these changes influence the process of metastasis development, we used a control group of patients. METHODS: We retrospectively identified 18 Luminal patients, for whom primary and metastatic tissue were available (cases) and 18 paired-matched patients (controls), not relapsed after at least 9 years of follow-up, and we quantified TILs and their composition (i.e. T CD8+ and CD4+/FOXP3+). The presence of TILs was defined as ≥10%. RESULTS: Our results showed that the microenvironment composition of relapsed patients was poor of TILs (median = 5%, I-III quartiles = 0.6-5%), CD8+ (2.5%, 0-5%) and CD4+/FOXP3 + (0%, 0-0.6%) in the primary tumor. Comparable results were observed in their related metastases (TILs 3.8%, 0.6-5%; CD8+ 0%, 0-1.3%; CD4+/FOXP3+ 0%,0-1.9%). On the contrary, the microenvironment in the control group was richer of TILs (5%, 5-17.5%) in comparison to cases, both in primary tumor (p = 0.035) and related metastases (p = 0.018). Although CD8+ in controls were similar to cases at primary tumor (p = 0.6498), but not at metastasis (p = 0.0223), they expressed only one part on the TILs subpopulations (p = 0.0060), while TILs in the cases at primary tumor were almost completely CD8+ (p = 0.5034). CONCLUSIONS: These findings suggest that the lack of activation of immune system in the primary tumor might influence the multifactor process of cancer progression.

Regorafenib in metastatic colorectal cancer.

Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis (VEGFR1, 2, 3; angiopoietin-1 receptor), oncogenesis (stem cell growth factor receptor; RET; BRAF including BRAFV600E), and tumor microenvironment (PDGFR-ß and FGFR). Based on data from the Phase III CORRECT study, regorafenib stands as a further option for patient affected by metastatic colorectal cancer who have exhausted previous available therapies. Its multi-targeted effect might explain activity in advanced lines of treatment, when cancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance, but also makes difficult to identify predictive biomarkers. In this article we examine preclinical as well as clinical data of regorafenib in the therapy of metastatic colorectal cancer, challenges for potential markers of efficacy and its role in the treatment algorithm.