Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Determinants of overall survival in patients with metastatic uveal melanoma.

BACKGROUND: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival. METHODS: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis. RESULTS: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively. CONCLUSIONS: Development of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death. PLAIN LANGUAGE SUMMARY: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.

Decision-Making and Health-Related Quality of Life in Patients with Melanoma Considering Adjuvant Immunotherapy.

BACKGROUND: Adjuvant anti-PD1 treatment improves relapse-free survival (RFS) but has not been shown to improve overall survival (OS) in melanoma and is associated with risks of immune-related adverse events (irAEs), some permanent. We identified factors patients consider in deciding whether to undergo adjuvant anti-PD1 treatment and assessed prospective health-related quality of life (HRQoL), treatment satisfaction, and decisional regret. PATIENTS AND METHODS: Patients with stage IIIB-IV cutaneous melanoma and free of disease, were candidates for adjuvant anti-PD1 immunotherapy, and had not yet discussed adjuvant treatment options with their oncologist were eligible. Participants viewed a 4-minute informational video tailored to their disease stage which communicated comprehensive, quantitative information about the risk of relapse both with and without adjuvant treatment, and risks of each irAE before deciding whether or not to opt for adjuvant therapy. We collected data on demographics, HRQoL, and attitudes toward adjuvant treatment over 1 year. RESULTS: 14/34 patients (41%) opted for adjuvant anti-PD1 immunotherapy, 20/34 (59%) opted for observation. Patients choosing adjuvant immunotherapy scored higher on HRQoL social well-being at pre-treatment, were more likely to endorse positive statements about adjuvant immunotherapy, and to perceive that their physician preferred adjuvant therapy. They had lower decisional regret and higher satisfaction, even if they experienced toxicity or recurrence. CONCLUSIONS: When provided with comprehensive quantitative information about risks and benefits of adjuvant anti-PD1 immunotherapy, 20/34 (59%) of patients opted for observation. Patients choosing adjuvant immunotherapy had lower decisional regret and higher satisfaction over time even if they had poorer outcomes in treatment.

Nivolumab versus placebo as adjuvant therapy for resected stage III melanoma: a propensity weighted indirect treatment comparison and number needed to treat analysis for recurrence-free survival and overall survival.

BACKGROUND: Recurrence-free survival (RFS) and overall survival (OS) data for adjuvant nivolumab versus placebo (proxy for routine surveillance) in patients with high-risk, resected melanoma are lacking. This post hoc, indirect treatment comparison (ITC) used pooled data from the phase 3 EORTC 18,071 (ipilimumab vs. placebo) and CheckMate 238 (nivolumab vs. ipilimumab) trials to assess RFS and OS with nivolumab versus placebo and the numbers needed to treat (NNT) over 4 years. METHODS: Patients with resected stage IIIB-C cutaneous melanoma (American Joint Committee on Cancer seventh edition) were included. Inverse probability treatment weighting (IPTW) was used to balance baseline characteristics. RFS NNTs were calculated for nivolumab versus ipilimumab and placebo. OS NNTs were calculated for nivolumab versus placebo. To adjust for different post-recurrence treatments, the difference in post-recurrence survival between the two ipilimumab arms was added to OS of the placebo arm. RESULTS: This ITC included 278, 643, and 365 patients treated with nivolumab, ipilimumab, and placebo, respectively. Following IPTW, nivolumab was associated with improved RFS versus placebo (hazard ratio [HR]: 0.49; 95% confidence interval [CI] 0.39-0.61) and ipilimumab (HR: 0.69; 95% CI 0.56-0.85). RFS NNT was 4.2 for nivolumab versus placebo and 8.9 for nivolumab versus ipilimumab. After post-recurrence survival adjustment, weighted 4-year OS rates were 75.8% for nivolumab and 64.1% for placebo; OS NNT for nivolumab versus placebo was 8.5. CONCLUSIONS: In patients with resected stage IIIB-C cutaneous melanoma in this ITC, nivolumab improved RFS versus placebo and ipilimumab, and OS versus placebo after post-recurrence survival adjustment.

Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response.

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

BACKGROUND: Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined. METHODS: We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients. Baseline patient and disease characteristics, and clinical outcomes were assessed. RESULTS: In the pooled analysis (N = 130), alterations in exons 11/13 had the highest response rates (38% and 33%); L576P (N = 23) and K642E (N = 12) mutations had ORR of 52% and 42%, respectively. ORR was 38% (mucosal), 25% (acral), and 8% (unknown-primary). PFS appeared longer in exon 11/13 vs. exon 17 alterations (median 4.3 and 4.5 vs. 1.1 months; p = 0.19), with similar superiority in OS (median 19.7 and 15.4 vs. 12.1 months; p = 0.20). By histology, median PFS was 4.5 months (mucosal), 2.7 (acral), and 5.0 (unknown-primary) [p = 0.36]. Median OS was 18.0 months (mucosal), 21.8 (acral), 11.5 (unknown-primary) [p = 0.26]. In multivariate analyses, mucosal melanoma was associated with higher PFS and exon 17 mutations were associated with reduced PFS. CONCLUSION: This multicenter study highlights KIT-alterations sensitive to imatinib and augments evidence for imatinib in subsets of KIT-altered melanoma.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Anorectal Mucosal Melanoma in the Era of Immune Checkpoint Inhibition: Should We Change Our Surgical Management Paradigm?

BACKGROUND: The advent of immune checkpoint inhibition therapy has dramatically improved survival in patients with skin melanoma. Survival outcomes after resection of anorectal melanoma treated with immune checkpoint inhibition have not been reported. OBJECTIVE: This study aimed to compare survival outcomes following surgical resection of anorectal melanoma between patients who received immune checkpoint inhibition and patients who did not. DESIGN: This study is a retrospective analysis of data from a prospectively maintained database. SETTING: This study was conducted at a comprehensive cancer center. PATIENTS: Patients who underwent surgery for anorectal melanoma between 2006 and 2017 were included. They were stratified according to the use of immune checkpoint inhibition. MAIN OUTCOME MEASURES: The primary outcomes measured were overall and disease-specific survival. RESULTS: Of the 47 patients included in the analysis, 29 (62%) received immune checkpoint inhibition therapy. Twenty-two (76%) of the 29 patients received immune checkpoint inhibition after detection of metastasis or disease progression rather than in the neoadjuvant or adjuvant setting. Overall survival did not differ significantly between patients who received immune checkpoint inhibition therapy and patients who did not (median, 52 and 20 months; 5-year rate, 41% vs 35%; p = 0.25). Disease-specific survival also did not differ significantly. Our analysis did not identify any clinical or pathological features associated with response to immune checkpoint inhibition therapy or with survival. LIMITATIONS: This study was limited by its relatively small sample and retrospective design and by the heterogeneous treatment regimen in the immune checkpoint inhibition group. CONCLUSIONS: Immune checkpoint inhibition therapy by itself does not appear to improve survival in patients who undergo resection or excision of anorectal melanoma. Combinations of immune checkpoint inhibition with other therapeutic modalities warrant further investigation. See Video Abstract at http://links.lww.com/DCR/B499. MELANOMA DE LA MUCOSA ANORRECTAL EN LA ERA DE LOS INHIBIDORES DEL PUNTO DE CONTROL INMUNOLÓGICO: ¿DEBEMOS DE CAMBIAR NUESTRO PARADIGMA DEL MANEJO QUIRÚRGICO: El advenimiento de la terapia de los inhibidores del punto de control inmunológico, han mejorado dramáticamente la supervivencia en pacientes con melanoma de piel. No se han informado los resultados de supervivencia después de la resección del melanoma anorrectal, tratado con inhibidores del punto de control inmunológico.Comparar los resultados de supervivencia después de la resección quirúrgica de melanoma anorrectal entre pacientes que recibieron y no recibieron inhibidores del punto de control inmunológico.Análisis retrospectivo de una base de datos mantenida prospectivamente.Centro oncológico integral.Pacientes que se sometieron a cirugía por melanoma anorrectal entre 2006 y 2017. Los pacientes fueron estratificados según el uso de inhibidores del punto de control inmunológico.Supervivencia global y específica de la enfermedad.De los 47 pacientes incluidos en el análisis, 29 (62%) recibieron terapia de inhibidores del punto de control inmunológico. Veintidós (76%) de los 29 pacientes recibieron inhibidores del punto de control inmunológico después de la detección de metástasis o progresión de la enfermedad, en vez de administración adyuvante o neoadyuvante. La supervivencia global no varió significativamente entre los pacientes que recibieron o no recibieron terapia de inhibidores del punto de control inmunológico (mediana, 52 y 20 meses, respectivamente; tasa a 5 años, 41% frente a 35%, respectivamente; p = 0,25). La supervivencia específica de la enfermedad tampoco varió significativamente. Nuestro análisis no identificó ninguna característica clínica o patológica, asociada con la respuesta a la terapia de inhibidores del punto de control inmunológico o con la supervivencia.Muestra relativamente pequeña y diseño retrospectivo. Régimen de tratamiento heterogéneo en el grupo de inhibidores del punto de control inmunológico.La terapia por sí sola, de inhibidores del punto de control inmunológico, no parece mejorar la supervivencia en pacientes que se someten a resección o escisión de melanoma anorrectal. Las combinaciones de inhibidores del punto de control inmunológico con otras modalidades terapéuticas, merecen una mayor investigación. Consulte Video Resumen en http://links.lww.com/DCR/B499. (Traducción-Dr. Fidel Ruiz Healy).

Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma.

Primary pulmonary melanoma (PPM) is an entity recognized by the thoracic WHO classification. However, given the absence of native melanocytes in the lung and the known phenomenon of regression of cutaneous melanomas, the existence of PPM has remained controversial. Herein we investigate clinicopathologic and genomic features of lung-only melanomas with the goal to clarify their site of origin. We identified 10 melanomas involving exclusively lung with no current or previous cutaneous, uveal, or mucosal primaries. Four patients had solitary lesions with mean size of 5.1 cm (range 3.0-10.1 cm), meeting the criteria of PPM. Four patients had 2-3 lesions and 2 patients had >10 lesions. All cases underwent targeted next-generation sequencing interrogating up to 468 cancer genes, which revealed mean tumor mutation burden of 42.6 per megabase (range 1.8 to 126) and frequent mutations involving BRAF, NRAS, NF1, KIT, and KRAS - a genomic profile typical of UV-associated cutaneous melanoma. Mutational signature was assessable for eight cases harboring >20 mutations. This revealed that all evaluable cases harbored a dominant UV signature. In addition, one nonevaluable case harbored a GG > AA TERT promoter variant that is highly specific for UV-mutagenesis. As control groups, using the same methodology, a dominant UV signature was identified in 97% (470/486) of cutaneous melanomas, whereas no lung adenocarcinoma (n = 291) exhibited this signature. Notably, the clinical and pathologic features of solitary melanomas, especially those with large size and epithelioid morphology, closely mimicked primary lung carcinomas, highlighting a major potential for misdiagnosis. In conclusion, presence of a UV signature provides direct evidence that nearly all lung-only melanomas in this series, including solitary lesions meeting the strict criteria of PPM, represent metastases from occult cutaneous melanomas. This suggests that lung-only melanomas should be considered as likely metastatic even in the absence of a known primary melanoma elsewhere.

Survival Outcomes After Metastasectomy in Melanoma Patients Categorized by Response to Checkpoint Blockade.

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001). CONCLUSIONS: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.

PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases. METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions ≥  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for ≥ 2 months. RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04). CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.

Isolated Abducens Nerve Palsy Following Pembrolizumab.

Pembrolizumab is a checkpoint inhibitor targeting the programmed cell death 1 receptor of lymphocytes and is used in the treatment of solid tumours including melanoma. The authors report a 64-year-old man treated with pembrolizumab for stage IV cutaneous melanoma (primary cutaneous melanoma of the right lower back) with liver metastases. The patient developed a horizontal binocular diplopia due to an isolated unilateral cranial nerve VI palsy. Following 1 week of high dose oral steroid therapy and cessation of the drug, the patient's nerve palsy and associated diplopic symptoms improved dramatically, and after 6 weeks of oral steroid taper and drug cessation, the palsy resolved completely. Few reports of checkpoint inhibitor autoimmune-induced isolated cranial nerve palsies have been described, and this is the first report of drug-induced isolated cranial nerve VI palsy.

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy.

BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.

Myocarditis Surveillance in Patients with Advanced Melanoma on Combination Immune Checkpoint Inhibitor Therapy: The Memorial Sloan Kettering Cancer Center Experience.

This letter to the editor describes myocarditis screening among patients undergoing combination immune checkpoint inhibitor therapy, in light of the consensus document from the Checkpoint Inhibitor Safety Working Group.

A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .