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Immune checkpoint inhibitor combinations have reshaped the treatment landscape of metastatic clear-cell renal cell carcinoma. As four regimens are now approved in the first-line setting, including nivolumab plus ipilimumab in intermediate and poor-risk patients, and pembrolizumab plus lenvatinib, nivolumab plus cabozantinib and pembrolizumab plus axitinib in all-comers, the choice of subsequent therapies is becoming a novel challenge for physicians. Such choices now rely on several compounds used as monotherapy which have demonstrated sustained activity after previous immune checkpoint or tyrosine kinase inhibitors. Future strategies may lie in novel targets, including hypoxia-inducible factor inhibitors, as well as further exploration of combinations in more advanced settings. Here we review the current evidence regarding treatment activity after immune checkpoint inhibitor combinations, the underlying biological and clinical challenges that may impact patient selection and the optimal sequencing strategies for clinical practice.

Cabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated.

ABSTRACTIntroduction:Osimertinib is a third-generation anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), that irreversibly binds to mutant EGFR, specifically to the T790M EGFR mutant non-small cell lung cancer (NSCLC). Since its approval, osimertinib has been tested in multiple scenarios, including the first-line and adjuvant setting of EGFR-mutant disease.Areas covered:The authors summarize the most recent evidence about osimertinib in NSCLC, covering its use as a first-line therapy, its activity on central nervous system metastatic disease, and in elderly patients. Moreover, the authors focus on resistance to this drug and on the therapeutic strategies that may be used to overcome this issue.Expert opinion:Osimertinib is a key player in the treatment ofEGFR mutant NSCLC and will probably be used in earlier clinical settings in the future, giving rise to an emerging variety of resistance mechanisms. These could be potentially overcome in several ways: e.g. as an oligo-progressive disease local therapy, maintaining osimertinib might be a reasonable option; however, for widespread progressive disease, a switch to chemotherapy should be considered. Finally, either liquid biopsy or tissue biopsy might be considered in patients progressing to osimertinib, as they can lead to the identification of potentially targetable resistance mechanisms.

The treatment landscape of metastatic renal cell carcinoma (mRCC), a chemotherapy-resistant disease, has dramatically changed in the last decade after the introduction of small molecule inhibitors targeting the vascular endothelial growth factor receptor and mammalian target of rapamycin kinases. The CheckMate 025 phase III trial in second line mRCC also introduced immunotherapy with immune-checkpoint inhibitors as an option in the management of mRCC. Both small molecules and immunotherapy are used as single agents and they are associated with different toxicities. Recent data demonstrated that the combination of 2 immunotherapies, nivolumab and ipilimumab, is more effective than tyrosine kinase inhibitors (TKI) monotherapy as first line treatment in intermediate and poor risk mRCC. Furthermore, combination of immunotherapies and TKI has been tested in several trials to evaluate if the combo with agents presenting a different mechanism of action is more effective than monotherapy with TKI. During the past several years, combined therapy of cytokines doublets or cytokines and bevacizumab doublets demonstrated little improvement in clinical outcomes and a relevant toxicity profile. Conversely, the combination of new agents has been recently shown to improve survival in patients with metastatic disease, thus changing the treatment landscape of mRCC. This comprehensive review aims at summarizing the recent advances in the treatment of mRCC.

ABSTRACTIntroductionPoly (ADP-ribose) polymerase inhibitors (PARPi) are already part of the armamentarium of drugs available against ovarian and breast cancer. There is less data available on the efficacy of these drugs in the treatment of non-small cell lung cancer (NSCLC).Areas coveredThe authors have analyzed the preclinical studies that justified the use of PARPi in NSCLC. They then evaluate the in vivo efficacy of the combination of these drugs with chemotherapy, radiotherapy, and immunotherapy.Expert opinionData from clinical trials available to date have discouraged the use of PARPi in association with chemotherapy or radiotherapy in NSCLC. The knowledge available to date opens the door to the use of PARPi in association with immunotherapy. In fact, the activity of these drugs would not be based only on direct cytotoxic action, but also on the modification of the intra-tumor microenvironment, in particular by increasing the expression of PD-L1 on tumor cells. This action might potentially enhance available treatments with a modest increase in toxicity.

Background: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months.Patients and methods: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival.Results: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis.Conclusion: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

The phase III PROSELICA trial showed that cabazitaxel 20 mg/m2(C20) was not inferior and better tolerated compared to cabazitaxel 25 mg/m2(C25) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed during or after docetaxel. Here, we report on a real-world retrospective analysis concerning the safety and the activity of C20 schedule in patients with mCRPC treated at our Institution. We identified 35 patients with mCRPC who received C20 as baseline dose treatment because they were frail or experienced serious toxicities to previous treatments. Adverse events assessment was performed at each visit during the treatment. Progression-free survival (PFS) and overall survival (OS) curves were obtained using the Kaplan–Meyer product-limit estimator. Median age was 71 years. All patients received a previous treatment with docetaxel; 19 patients (54%) received one additional line of therapy and 9 (26%) two or more. Patients received a median of 4 cycles (range: 2–10). Only one patient experienced grade 3 neutropenia (3%), two patients grade 3 anemia (6%), and one patient grade 3 fatigue (3%); three patients were treated with prophylactic Granulocyte colony-stimulating factor (9%). The most frequent adverse events of all grades were: anemia (39%), fatigue (33%), and diarrhea (15%). Median PFS was 3.7 months [95% confidence interval (CI): 3.31–4.09]; median OS was 10.3 months (95% CI: 4.63–15.97). Our real-world analysis confirms that C20 is a feasible option for elderly and heavily pretreated patients with mCRPC, showing activity and good tolerability.

Small-cell carcinoma of the bladder (SCCB) is a rare, highly aggressive, neoplasm. We retrospectively analyzed the Surveillance, Epidemiology, and End Results (SEER) database to investigate the impact of chemotherapy, surgery, and radiotherapy on overall survival (OS) of patients with non-metastatic SCCB.

We retrospectively investigated the prognostic significance of periostin, an extracellular matrix protein, in tumor biopsy samples of 215 patients with prostate cancer. We found that periostin expression can predict the outcome of specific subgroups of patients. In addition to the prostate-specific antigen level and/or Gleason score, the immunohistochemical assessment of periostin expression could be useful in clinical practice to predict the prognosis.