Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). INTERPRETATION: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. FUNDING: Merck Sharp & Dohme.

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant. INTERPRETATION: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. FUNDING: Merck Sharp & Dohme.

Personalized treatment is better than one treatment fits all in the management of patients with mCRC: a consensus statement.

The VEGF- (bevacizumab) and EGFR- (cetuximab and panitumumab) targeting monoclonal antibodies have become integral components of the first-line treatment strategies for patients with metastatic colorectal cancer (mCRC). Increasingly combination chemotherapy, with or without a targeted agent, is being used to facilitate curative liver resection and improve survival rates in patients with initially unresectable but potentially resectable mCRC. Currently, the only selective marker for the treatment of patients with mCRC is tumor RAS mutational status. BRAF status is a strong prognostic indicator. Medical and clinical oncologists from Central Asia, Russia, the Middle East, Africa and Turkey reviewed data for the use of targeted agents in the treatment of patients with mCRC and have formed recommendations for the biological of choice first-line for patients with mCRC.

Cytoreductive surgery in patients with recurrent or metastatic gastrointestinal stromal tumors sensitive to imatinib: a retrospective analysis of two Russian cancer centers.

Background: The role of cytoreductive surgery for patients with recurrent or metastatic gastrointestinal stromal tumors (mGISTs) responding to imatinib (IM) has not yet been established. We carried out a retrospective analysis of the outcomes of patients with mGISTs in two Russian cancer centers. We compared two cohorts: treated (Group S) or not treated with surgery (Group NS) after a partial response (PR) or stable disease (SD) while on IM. Methods: A total 44 patients treated by IM as first line treatment were included in our analysis. Prognostically similar patients only sensitive to IM cases with hepatic or peritoneal metastases as well as durable response to IM lasting more than 12 months were included in a control arm. Patients in Group NS received only IM until disease progression. Patients in Group S were treated additionally with metastasectomy after having response or SD on IM. Results: The baseline characteristics were similar between the groups with several trends: a higher proportion of patients achieved a PR in Group S (87% vs. 55%, P=0.165), and greater number of patients had peritoneal metastases in Group NS (45% vs. 27%, P=0.759). The median time to surgery from the initiation of IM was 8 months. Progression-free survival (PFS) and overall survival (OS) were significantly longer in Group S than Group NS: the median PFS was 78 vs. 35 months (P=0.088); the median OS was 141 vs. 80 months (P=0.154). Conclusions: The surgical resection of residual lesions after disease control with IM is likely to be beneficial to patients with mGISTs.

Prognostic and predictive value of non-steroidal anti-inflammatory drugs in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

BACKGROUND: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. PATIENTS AND METHODS: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. RESULTS: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53). CONCLUSION: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab.

Prognostic and predictive value of metformin in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

BACKGROUND: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. METHODS: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation. RESULTS: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52-1.45) and DMFS (HR 0.82, 95% CI 0.47-1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37-1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56-1.69). CONCLUSIONS: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma.

Prognostic and predictive value of ß-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

BACKGROUND: ß-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of ß-adrenoreceptor blockade by ß-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. METHODS: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). ß-blocker use was defined as oral administration of any ß-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of ß-blockers and RFS. RESULTS: Ninety-nine (10%) of 1019 randomised patients used ß-blockers at baseline. ß-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with ß-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among ß-blocker users and 0.59 (95% CI 0.48-0.71) among those not using ß-blockers. CONCLUSIONS: This study suggests no prognostic effect of ß-blockers in resected high-risk stage III melanoma. However, ß-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with ß-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma.

BACKGROUND: In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence- and distant metastasis-free survival than placebo in patients with resected high-risk stage III melanoma. To confirm the stability of these benefits, longer-term data were needed. METHODS: We randomly assigned 1019 patients to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) and had previously reported data with a 15-, 36-, and 42-month median follow-up. We now report data at a median follow-up of 4.9 years. We report a number of outcomes, including recurrence-free survival in the overall population and in the subgroup of patients with cancer who were positive for the programmed death-ligand 1 (PD-L1). Distant metastasis-free survival was a secondary end point. RESULTS: In the overall intention-to-treat population, pembrolizumab was still associated with longer recurrence-free survival than placebo (5-year rate of recurrence-free survival, 55.4% [95% confidence interval (CI), 50.8 to 59.8] vs. 38.3% [95% CI, 33.9 to 42.7]; hazard ratio for recurrence or death, 0.61 [95% CI, 0.51 to 0.72]) and a longer distant metastasis-free survival (5-year rate of distant metastasis-free survival, 60.6% [95% CI, 56.0 to 64.9] vs. 44.5% [95% CI, 39.9 to 48.9]; hazard ratio for distant metastasis or death, 0.62 [95% CI, 0.52 to 0.75]). Similar findings were obtained in the subgroup of 853 patients with PD-L1­positive tumors. CONCLUSIONS: The 5-year analysis of adjuvant therapy with pembrolizumab resulted in a sustained improvement in the long-term recurrence- and distant metastasis-free survival compared with placebo in patients with resected stage III melanoma. (Funded by Merck & Co., Inc.; ClinicalTrials.gov number, NCT02362594, and EudraCT number, 2014-004944-37.)

Combined anti-HER2 and hormonal treatment in a patient with HR+HER2+ clear-cell uterine carcinoma: A case report.

Clear-cell carcinoma (CCC) of the uterus is an aggressive disease. Current international guidelines on the treatment of uterine carcinomas predominantly cover cancer with endometrioid histology, and clinicians tend to use the same approach for patients with non-endometrioid histology due to the absence of separate guidelines for these rare tumor types. At present, molecular analysis enables the assessment of novel and non-standard treatment options based on the individual characteristics of a tumor. The present report presents a clinical case of successful treatment of a patient with clear cell uterine carcinoma with HER2 and ER expression. Non-toxic targeted treatment was used based on immunohistochemistry (IHC) data. The patient received anti-HER2 and hormonal treatment and demonstrated an excellent response. The follow-up period was 47 months and the patient remained stable during treatment without significant toxicity. Therefore, this approach demonstrated the potential for selecting highly-specific therapy for rare tumors, which lack distinct recommendations for their treatment.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.

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 < .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 > 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/K v 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.

Humoral immune response to thymidylate synthase in colon cancer patients after 5-FU chemotherapy.

Thymidylate synthase (TYMS), the critical enzyme for DNA synthesis and a target for chemotherapy, was recently characterized as an oncogene and a potential target for specific immunotherapy. Here we report TYMS-specific antibody response in a fraction of colon cancer patients. Humoral immune response to TYMS is induced by chemotherapy using TYMS inhibitors, such as 5-fluorouracil (5-FU), and may be associated with tumor burden. Therefore, TYMS may serve as a useful serological biomarker for monitoring the course of disease and treatment in cancer patients.

Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients.

Antibodies to cancer antigens can often be detected in the sera of patients, although the mechanism of the underlying humoral immune response is poorly understood. Using immunoscreening of tumor-derived cDNA expression libraries (SEREX), we identified human histone deacetylase 3 (HDAC3) as serologically defined antigen in colon cancer. Closely related HDAC1 and HDAC2 do not elicit humoral response in colon cancer patients. We show that the C-terminal region of HDAC3 protein lacking the homology to other Class I HDAC contains at least 3 distinct B-cell epitopes that are recognized by the serum antibodies. HDAC3 in combination with other SEREX antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients.