Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study.

OBJECTIVE: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. METHODS: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. RESULTS: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR. CONCLUSIONS: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.

Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.

BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.

Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance)☆.

BACKGROUND: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer. PATIENTS AND METHODS: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. RESULTS: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (<4 positive lymph nodes) and 200 (38.5%) were pN2 (≥4 positive lymph nodes). The presence of TD was associated with poorer DFS [adjusted hazard ratio (aHR) = 1.63, 95% CI 1.33-1.98] and OS (aHR = 1.59, 95% CI 1.24-2.04). The negative effect of TD was observed for both pN1a/b and pN2 groups. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Combining TD and the number of lymph node metastases, 104 of 1470 (7.1%) pN1 patients were re-staged as pN2, with worse outcomes than patients confirmed as pN1 (3-year DFS rate: 65.4% versus 80.5%, P = 0.0003; 5-year OS rate: 87.9% versus 69.1%, P = <0.0001). DFS was not different between patients re-staged as pN2 and those initially staged as pN2 (3-year DFS rate: 65.4% versus 62.3%, P = 0.4895). CONCLUSION: Combining the number of TD and the number of lymph node metastases improved the prognostication accuracy of tumor-node-metastasis (TNM) staging.

Pancreatic neuroendocrine tumors: Challenges in an underestimated disease.

Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET.