ABSTRACT
PURPOSE: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy. PATIENTS AND METHODS: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy). RESULTS: Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS. CONCLUSION: Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.
Subject(s)
Basal Cell Nevus Syndrome , Consensus , Hedgehog Proteins , Skin Neoplasms , Humans , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/metabolism , Basal Cell Nevus Syndrome/drug therapy , Basal Cell Nevus Syndrome/diagnosis , Basal Cell Nevus Syndrome/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/diagnosis , Skin Neoplasms/pathology , Anilides/therapeutic use , Pyridines/therapeutic use , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. METHODS: Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). RESULTS: Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. CONCLUSION: QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Merkel Cell , Ipilimumab , Nivolumab , Quality of Life , Radiosurgery , Skin Neoplasms , Humans , Ipilimumab/administration & dosage , Ipilimumab/adverse effects , Ipilimumab/therapeutic use , Nivolumab/therapeutic use , Nivolumab/adverse effects , Nivolumab/administration & dosage , Carcinoma, Merkel Cell/therapy , Carcinoma, Merkel Cell/pathology , Male , Female , Aged , Skin Neoplasms/therapy , Skin Neoplasms/pathology , Skin Neoplasms/drug therapy , Radiosurgery/adverse effects , Radiosurgery/methods , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Patient Reported Outcome MeasuresABSTRACT
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vd1 gd T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial transcriptomics demonstrated co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vd1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.
ABSTRACT
In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.
ABSTRACT
PURPOSE: Little is known about late and long-term patient-reported outcomes (PROs) of immune checkpoint modulators (ICMs) outside clinical trials. We conducted a cross-sectional, mixed-methods study to describe long-term PROs among advanced melanoma patients who began standard of care treatment with ICMs at least 1 year previously. METHODS: All participants completed the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM), assessing 46 immune-related side effects on a 5-point Likert scale, and a subset completed individual interviews. Descriptive statistics were computed for quantitative data and applied thematic analysis was used to examine qualitative data. RESULTS: Participants (N = 80) had a mean age of 67 years, and the majority were male (66%), non-Hispanic White (96%), and college graduates (61%). Single-agent nivolumab was the most common first (47%) and current/recent ICM (64%). On the FACT-ICM, 98% of participants reported at least one side effect, and 78% reported moderate or severe side effects. The most common moderate or severe side effects were aching joints (43%) and fatigue (38%). In interviews (n = 20), we identified five themes regarding patients' longer-term experiences after ICMs: lasting fatigue or decline in functioning, minimal side effects, manageable thyroid and pituitary dysfunction, skin conditions can be difficult to manage, and treating the cancer is worth the side effects. CONCLUSIONS: Nearly all patients reported side effects of ICMs at least 1 year after starting treatment. Our findings suggest that ICM side effect screening and management-especially for aching joints and fatigue-are indicated during long-term care of people living with advanced melanoma.
Subject(s)
Immune Checkpoint Inhibitors , Melanoma , Patient Reported Outcome Measures , Humans , Melanoma/drug therapy , Male , Female , Aged , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Cross-Sectional Studies , Middle Aged , Neoplasm Recurrence, Local , Adult , Aged, 80 and over , Skin Neoplasms/drug therapy , Quality of LifeABSTRACT
IFx-Hu2.0 was designed to encode part of the Emm55 protein contained within a plasmid in a formulation intended for transfection into mammalian cells. IFx-Hu2.0 promotes both adaptive and innate immune responses in animal studies. Furthermore, previous studies have demonstrated safety/efficacy in equine, canine, and murine species. We present the first-in-human study of IFx-Hu2.0, administered by intralesional injection into melanoma tumors of seven patients with stage III/IV unresectable melanoma. No dose-limiting toxicities attributable to IFx-Hu2.0 were observed. Grade 1/2 injection site reactions were observed in five of seven patients. IgG and IgM responses to Emm55 peptides and known melanoma antigens were seen in the peripheral blood, suggesting that IFx-Hu2.0 acts as an individualized "in situ vaccine." Three of four patients previously refractory to anti-PD1 experienced clinical benefit upon subsequent anti-PD1-based treatment. Therefore, this approach is feasible, and clinical/correlative outcomes warrant further investigation for treating patients with metastatic melanoma with an immune priming agent.
Subject(s)
Melanoma , Neoplasm Staging , Humans , Melanoma/drug therapy , Melanoma/immunology , Melanoma/pathology , Female , Male , Middle Aged , Aged , Cancer Vaccines/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/therapeutic use , AdultABSTRACT
BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Head and Neck Neoplasms , Lung Neoplasms , Melanoma , Humans , Nivolumab/pharmacology , Nivolumab/therapeutic use , Cetuximab/pharmacology , Cetuximab/therapeutic use , Lung Neoplasms/chemically induced , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Head and Neck Neoplasms/drug therapyABSTRACT
PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.
Subject(s)
Antineoplastic Agents, Immunological , Brain Neoplasms , Melanoma , Radiosurgery , Humans , Ipilimumab/therapeutic use , Melanoma/pathology , Nivolumab/therapeutic use , Radiosurgery/methods , Prospective Studies , Antineoplastic Agents, Immunological/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Retrospective StudiesABSTRACT
PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.
Subject(s)
Cell-Free Nucleic Acids , Kidney Neoplasms , Kidney Transplantation , Melanoma , Adult , Humans , Nivolumab/therapeutic use , Ipilimumab/therapeutic use , Tacrolimus/adverse effects , Prednisone/therapeutic use , Kidney Transplantation/adverse effects , Prospective Studies , Creatinine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Melanoma/pathology , Kidney Neoplasms/pathologyABSTRACT
BACKGROUND: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors. METHODS: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design. RESULTS: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells. CONCLUSIONS: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.
Subject(s)
Exanthema , Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Vemurafenib , Proto-Oncogene Proteins B-raf , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Protein Kinase Inhibitors/adverse effects , Exanthema/chemically induced , Exanthema/drug therapy , Heat-Shock Proteins/genetics , Heat-Shock Proteins/therapeutic use , Mitogen-Activated Protein Kinase Kinases/genetics , Mutation , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathologyABSTRACT
Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.
Melanoma is a serious form of skin cancer that develops from melanocytes, which are pigment cells that give the skin, hair, and other tissues their color. At advanced stages of spread, melanoma can be life-threatening. However, immunotherapy, a type of therapy that helps the body's immune system to destroy cancer cells, allows some patients with advanced melanoma to live longer. The OPTIMIzE study looked at how well patients with advanced melanoma did when treated with different immunotherapies. These patients were treated in a real-world setting, such as a doctor's office, and were not participating in a clinical trial. Compared with clinical trials, real-world studies like the OPTIMIzE study may include a more varied group of patients because of the less selective study enrollment requirements. In the OPTIMIzE study, patients were treated with either a single immunotherapy (nivolumab or pembrolizumab alone) or a combination of two immunotherapies (nivolumab plus ipilimumab). Both single and combination immunotherapies were effective and tolerable. Patients receiving nivolumab plus ipilimumab had greater tumor shrinkage than patients receiving nivolumab or pembrolizumab alone, but with more side effects from their treatment. Despite the occurrence of side effects with both single and combination immunotherapies, patients reported that their quality of life remained stable while being treated. The OPTIMIzE study shows that immunotherapy is effective and tolerable for patients with advanced melanoma in the real-world setting. This information may help doctors with selecting treatments for their patients with advanced melanoma. Clinical Trial Registration: NCT02780089 (ClinicalTrials.gov).
Subject(s)
Melanoma , Humans , Melanoma/drug therapy , Nivolumab/adverse effects , Ipilimumab/adverse effects , Quality of Life , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , RegistriesABSTRACT
Since the US Food and Drug Administration first approved talimogene laherparepvec for the treatment of melanoma in 2015, the field of oncolytic immunotherapy (OI) has rapidly evolved. There are numerous ongoing clinical studies assessing the clinical activity of OIs across a wide range of tumor types. Further understanding of the mechanisms underlying the anti-tumor immune response has led to the development of OIs with improved immune-mediated preclinical efficacy. In this review, we discuss the key approaches for developing the next generation of herpes simplex virus-based OIs. Modifications to the viral genome and incorporation of transgenes to promote safety, tumor-selective replication, and immune stimulation are reviewed. We also review the advantages and disadvantages of intratumoral versus intravenous administration, summarize clinical evidence supporting the use of OIs as a strategy to overcome resistance to immune checkpoint blockade, and consider emerging opportunities to improve OI efficacy in the combination setting.
ABSTRACT
BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Male , Female , Aged , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/etiology , Neoadjuvant Therapy/adverse effects , Follow-Up Studies , Skin Neoplasms/drug therapy , Skin Neoplasms/surgery , Neoplasm Staging , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.
Subject(s)
Brain Neoplasms , Melanoma , Radiation Injuries , Radiosurgery , Humans , Proto-Oncogene Proteins B-raf/genetics , Radiosurgery/adverse effects , Brain Neoplasms/therapy , Melanoma/therapy , Protein Kinase Inhibitors/adverse effects , Necrosis , Mitogen-Activated Protein Kinase KinasesABSTRACT
PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. RESULTS: The updated review identified 21 additional randomized trials. UPDATED RECOMMENDATIONS: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.
Subject(s)
Melanoma , Oncolytic Virotherapy , Skin Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ipilimumab/therapeutic use , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Nivolumab/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Melanoma, Cutaneous MalignantABSTRACT
In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .
Subject(s)
Melanoma , Nivolumab , Humans , B7-H1 Antigen , CTLA-4 Antigen , Ipilimumab/adverse effects , Ipilimumab/therapeutic use , Melanoma/drug therapy , Nivolumab/adverse effects , Nivolumab/therapeutic useABSTRACT
PURPOSE: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. METHODS: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses. RESULTS: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02. CONCLUSION: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.
Subject(s)
Melanoma , Nivolumab , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ipilimumab , Melanoma/pathology , Nivolumab/therapeutic useABSTRACT
To provide guidance to clinicians regarding the use of systemic therapy for melanoma. American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. The updated review identified 21 additional randomized trials. Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on antiPD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies. This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update. Additional information is available at www.asco.org/melanoma-guidelines
Subject(s)
Humans , Antineoplastic Agents, Immunological , Melanoma/immunology , Nivolumab/therapeutic use , Mutation/immunologyABSTRACT
While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.