Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in ...melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy.
Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR.
Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes.
To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.
Solitary fibrous tumor (SFT) is a mesenchymal neoplasm of fibrous origin. The 2013 WHO classification of soft tissue tumors defines malignant forms as hypercellular, mitotically active (>4 mitosis/10 ...high-power fields), with cytological atypia, tumor necrosis, and/or infiltrative margins. With an IRB-approved protocol, we investigated patient records and clinicopathologic data from our Sarcoma Database to describe the clinical characteristics of both benign and malignant SFT. All pathology specimens were reviewed by two pathologists. Descriptive statistics and univariate/multivariate survival analysis were performed. Patient records and Social Security Death Index were used to evaluate vital status. Of 82 patients, 47 (57%) were women and 73 (89%) were Caucasian. Median age was 62 years (range, 20 to 89). Thirty-two (39%) patients succumbed to the disease. Primary tumor site was lung/pleura in 28 (34%), abdomen/pelvis in 23 (28%), extremity in 13 (16%), and head/neck in 9 (11%) patients. Pathology was described as benign in 42 (51%) and malignant in 40 (49%) patients. Compared to benign SFT, malignant histology is associated with larger tumor size, higher mitotic counts, metastatic disease at diagnosis, and greater use of chemotherapy and radiation therapy. Gender, age, and tumor site were not significantly different between benign and malignant subtypes. By univariate analysis, only benign vs. malignant variant and complete resection positively impacted overall survival (P = 0.02 and P<0.0001, respectively). In the multivariable analysis of overall survival, receiving chemotherapy or not receiving surgery were two variables significantly associated with higher failure rate in overall survival: patients with chemotherapy vs. no chemotherapy (P = 0.003, HR = 4.55, with 95% CI: 1.68-12.34) and patients without surgery vs. with surgery (P = 0.005, HR = 25.49, with 95% CI: 2.62-247.57). Clear survival differences exist between benign and malignant SFT. While surgery appears to be the best treatment option for benign and malignant SFT, better systemic therapies are needed to improve outcomes of patients with metastatic, malignant SFT.
Merkel cell carcinoma (MCC) has a high risk of recurrence after initial surgical therapy. Adjuvant radiation therapy (RT) and chemotherapy may be used to reduce the risk of locoregional and systemic ...recurrence, respectively, but there are conflicting data regarding their impact on survival. We performed a retrospective analysis of MCC cases from the National Cancer Data Base (NCDB) to assess whether adjuvant therapy was associated with differences in survival.
Six thousand nine hundred and eight MCC patients with staging, treatment, and survival data were included. Multivariable analyses were conducted for overall survival (OS) with various treatment modalities while adjusting for prognostic variables including age, sex, comorbidities (Charlson/Deyo score), margin status, primary tumor site and size, and lymph node status. All statistical tests were two-sided.
For localized MCC (stage I: n = 3369, stage II: n = 1474 ), surgery plus adjuvant RT was associated with statistically significantly better OS than with surgery alone in multivariable analyses (stage I: hazard ratio HR = 0.71, 95% confidence interval CI = 0.64 to 0.80, P < .001; stage II: HR = 0.77, 95% CI = 0.66 to 0.89, P < .001). In patients with regional nodal metastases (stage III: n = 2065 ), neither adjuvant RT nor chemotherapy was associated with statistically significantly improved or worsened OS.
In this study of the largest MCC cohort reported to date, adjuvant RT was associated with improved OS in stages I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MCC. These results, with the limitations of retrospective analyses, are consistent with earlier studies suggesting benefit with adjuvant RT but do not support the routine use of adjuvant chemotherapy in MCC.
Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the ...transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets.
We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell-cell interactions were inferred and compared with those in nonacral cutaneous melanoma.
Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells.
Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation.
To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database.
The melanoma staging recommendations ...were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria.
Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.
Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.
Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as ...adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.
In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12–17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual.
Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52–69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months IQR 10·2–18·7 in the pembrolizumab group and 14·3 months 10·1–18·7 in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio HR 0·65 95% CI 0·46–0·92; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months 16·7–25·3 in the pembrolizumab group and 20·9 months 16·6–25·3 in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 95% CI 0·45–0·82). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3–4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred.
Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile.
Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and ...secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps. In most cases, paradoxical MAPK activation--resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms--seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced SCCs, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear. In this Review, we describe the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. We discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.
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