Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

BACKGROUND The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrencefree survival than placebo, with no new toxic effects identified.

Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: Updated results from the EORTC 1325-MG/KEYNOTE-054 trial

PURPOSE: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P \u3c .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis \u3e 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. RESULTS: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/Kv wild type). CONCLUSION: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups

Adjuvant pembrolizumab versus placebo in resected stage III melanoma

The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74;

Primary malignant melanoma of the vagina: A case report

Malignant primary melanoma of the vagina (PMV) is a rare type of non-cutaneous melanoma often discovered in postmenopausal women. PMV has a very aggressive disease course and a poor prognosis. The best course of treatment is not presently agreed upon. In this report, we describe the case of a 68-year-old woman presenting with a malignant PMV and its subsequent management. The patient presented with right vaginal pain, abnormal vaginal bleeding and a new vaginal mass. A PET scan identified a 28 × 38 mm hypermetabolic vaginal lesion, without nodal involvement or distant metastasis. A posterior exenteration type 2B was performed, including the anal mucosa. Sentinel lymph node dissection, vaginal and rectal resection as well as a terminal colostomy were also carried out. Final staging was FIGO stage III and T4bN1. Four months later, the patient presented with a recurrent vaginal bleed and intra-vaginal induration. Imaging revealed loco-reginal recurrence at the site of the primary malignancy with countless metastases. The patient opted for palliative care given the early disseminated recurrence and her multiple comorbidities. We review the treatment options for PMV, mainly the importance of surgery as the mainstay of treatment as well as the interest of adding checkpoint inhibitor immunotherapy or targeted therapy to the treatment plan. We also summarize the characteristics of PMV and its main prognostic factors

Upfront <i>DPYD</i> Genotyping and Toxicity Associated with Fluoropyrimidine-Based Concurrent Chemoradiotherapy for Oropharyngeal Carcinomas: A Work in Progress

Background: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided

Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma

Abstract Background The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. Method This is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3–5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria. Discussion The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC. Trial registration NCT03283605. Registration date: September 14, 2017; version 1

Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma

Abstract Background The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. Method This is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3–5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria. Discussion The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC. Trial registration NCT03283605. Registration date: September 14, 2017; version 1