Immunological backbone of uveal melanoma: is there a rationale for immunotherapy?

No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease

Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In an advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in OC. Methods: We searched PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were identified, of which 16 were phase I or II and 4 phase III trials. These trials used ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab). There was no reported improvement in survival, and some trials were terminated early due to toxicity or lack of response. Combining ICIs with chemotherapy, anti-VEGF therapy, or PARP inhibitors improved response rates and survival in spite of a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of OC might lead to better treatment options and facilitate the design of tailored trials

The Interplay between PARP Inhibitors and Immunotherapy in Ovarian Cancer: The Rationale behind a New Combination Therapy

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting

Ovarian cancer (OC) is the eighth most common cancer among the female population and the most lethal of all the female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC in the maintenance setting post platinum-based chemotherapy. Niraparib is the first Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved PARPi as maintenance therapy for platinum-sensitive OC, regardless of BReast CAncer gene (BRCA) status, in first-line patients, with a recent restriction to germline BRCA mutations in second-line patients. In this review, we comprehensively summarized the pharmacological properties of niraparib, alongside the efficacy and safety data of the main trials leading to the current approvals, and discussed the future development of this agent

The Interplay between Anti-Angiogenics and Immunotherapy in Colorectal Cancer

Angiogenesis, a hallmark of cancer, plays a fundamental role in colorectal cancer (CRC). Anti-angiogenic drugs and chemotherapy represent a standard of care for treating metastatic disease. Immune checkpoint inhibitors (ICIs) have changed the therapeutic algorithm of many solid tumors. However, the efficacy of ICIs is limited to mCRC patients carrying microsatellite instability (MSI-H), which represent approximately 3–5% of mCRC. Emerging evidence suggests that anti-angiogenic drugs could exhibit immunomodulatory properties. Thus, there is a strong rationale for combining anti-angiogenics and ICIs to improve efficacy in the metastatic setting. Our review summarizes the pre-clinical and clinical evidence regarding the combination of anti-angiogenics and ICIs in mCRC to deepen the possible application in daily clinical practice

Beyond Platinum, ICIs in Metastatic Cervical Cancer: A Systematic Review

Background: Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety. Methods: The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs). Results: A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6–94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs. Conclusion: Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival

The Interplay between PARP Inhibitors and Immunotherapy in Ovarian Cancer: The Rationale behind a New Combination Therapy

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies

Immune-Checkpoint Inhibitors in Advanced Bladder Cancer: Seize the Day

Background: In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many solid tumors. Our review aims to summarize the main findings regarding the clinical use of ICIs in advanced BCa. Methods: We searched PubMed, Embase, and Cochrane databases, and conference abstracts from international congresses (ASCO, ESMO, ASCO GU) for clinical trials, focusing on ICIs as monotherapy and combinations in metastatic BCa. Results: 18 studies were identified. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were used. Survival outcomes have been improved by second-line ICIs, whereas first-line results are dismal. Avelumab maintenance in patients obtaining disease control with chemotherapy has achieved the highest survival rates. Conclusions: ICIs improve survival after platinum-based chemotherapy. Avelumab maintenance represents a new practice-changing treatment. The combinations of ICIs and other compounds, such as FGFR-inhibitors, antibody-drug conjugates, and anti-angiogenic drugs, represent promising therapeutic approaches. Biomarkers with predictive roles and sequencing strategies are warranted for best patient selection

Clinic, Endoscopic and Histological Features in Patients Treated with ICI Developing GI Toxicity: Some News and Reappraisal from a Mono-Institutional Experience

Background: Immune checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different solid tumors over the last ten years. Gastrointestinal (GI) adverse events (AEs), such as diarrhea and colitis, occur in up to 50% of patients treated with ICIs. Materials and methods: We conducted a single-center retrospective analysis in patients with solid tumors treated with ICIs in a 6-year period, from 2015 to 2021, developing GI AEs, for which an endoscopic analysis was performed, with available histological specimens or surgery. Results: Twenty-one patients developed GI AEs under ICIs. The median time from the start of ICIs to the onset of GI AEs was 5 months. Diarrhea was the most frequent symptom (57.2%), upper GI symptoms presented in four patients (19%), while three patients (14.3%) had no symptoms and were diagnosed occasionally. Two patients underwent surgical resection for acute abdomen. Histological findings observed in endoscopic sampling were eosinophilic-pattern gastro-enterocolitis, apoptotic damage, IBD-like features, and ischemic-like changes. Histological damage was also documented in patients with unremarkable endoscopy. Conclusions: Under ICI therapy, GI toxicity is an expected event. Since GIAEs can mimic a broad range of primary GI diseases, a multidisciplinary approach is advocated with upper and lower GI mucosal sampling to remodel therapy and avoid complications