Multiple immune-related adverse events secondary to checkpoint inhibitor therapy in patients with advanced cancer: association with treatment effectiveness.

Introduction: Checkpoint inhibitors (CPI) are widely used in cancer treatment with a potential of causing immune-related adverse events (IRAEs). Several studies have reported a positive correlation between development of IRAEs and improved survival outcome. However, few studies have focused on the potential role of multiple IRAEs on treatment effectiveness. This study aimed at investigating the association between multiple IRAEs and treatment effectiveness in terms of progression-free survival (PFS) and overall survival (OS) in advanced cancer patients. Methods: We performed a retrospective cohort study at three Swedish centers. All patients (n=600) treated with PD-L1 or PD-1 inhibitor, in monotherapy or in combination for advanced cancer between January 2017 and December 2021 were included. Multiple IRAEs were defined as IRAEs involving more than one organ system either simultaneously or sequentially. Time-depending Cox-regression model to mitigate the risk for immortal time bias (ITB) was applied. Results: The major tumor types were non-small cell lung cancer (205 patients; 34.2%) and malignant melanoma (196 patients; 32.7%). Of all patients,32.8% developed single IRAE and 16.2% multiple IRAEs. Patients with multiple IRAEs showed significantly improved PFS (Hazard Ratio, HR=0.78 95% Confidence Interval, CI: 0.57-0.98) and OS (HR=0.65 95% CI: 0.44-0.95) compared to patients with single IRAE or no IRAE (HR=0.46 95% CI:0.34-0.62 for PFS vs HR=0.41 95% CI: 0.28-0.60 for OS). Conclusion: In conclusion, our data supports a stronger association between development of multiple as opposed to single IRAEs and clinical effectiveness in advanced cancer patients treated with CPIs.

Association between parity and pregnancy-associated tumor features in high-grade serous ovarian cancer.

PURPOSE: High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer subtype. Parity is an important risk-reducing factor, but the underlying mechanism behind the protective effect is unclear. Our aim was to study if the expression of hormones and proteins involved in pregnancy were affected by the woman's parity status, and if they may be associated with tumor stage and survival. METHODS: We evaluated expression of progesterone receptor (PR), progesterone receptor membrane component 1 (PGRMC1), relaxin-2, and transforming growth factor beta 1 (TGFß1) in tumor tissue from 92 women with HGSC parous (n = 73) and nulliparous (n = 19). Key findings were then evaluated in an independent expansion cohort of 49 patients. Survival rates by hormone/protein expression were illustrated using the Kaplan-Meier method. The independent prognostic value was tested by Cox regression, using models adjusted for established poor-prognostic factors (age at diagnosis, FIGO stage, type of surgery, and macroscopic residual tumor after surgery). RESULTS: HGSC tumors from parous women were PR positive (≥ 1% PR expression in tumor cells) more often than tumors from nulliparous women (42% vs. 16%; p-value 0.04), and having more children was associated with developing PR positive tumors [i.e., ≥ 3 children versus nulliparity, adjusted for age at diagnosis and stage: OR 4.31 (95% CI 1.12-19.69)]. A similar result was seen in the expansion cohort. Parity status had no impact on expression of PGRMC1, relaxin-2 and TGFß1. No associations were seen with tumor stage or survival. CONCLUSION: Tumors from parous women with HGSC expressed PR more often than tumors from nulliparous women, indicating that pregnancies might possibly have a long-lasting impact on ovarian cancer development.

The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients: A case series and meta-analysis.

Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta-analysis. Thirty-five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real-world progression-free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta-analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real-world response rate to chemotherapy for the prior-CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04-4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era.