The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Objective
This study aims to describe the overall survival (OS) and to identify associated prognostic factors in patients with inoperable and metastatic cutaneous melanoma of the head and neck (H&N) ...region, undergoing modern systemic treatments.
Methods
This is a retrospective single institutional study. Data on all consecutive H&N melanoma patients treated with systemic oncologic treatments between 2015 and 2022 were collected from electronic medical files. Kaplan–Meier curves were used to describe survival and Cox regression analysis was used to identify patient and tumor factors associated with prognosis.
Results
A total of 144 patients were included. Median OS was 45 months (95% confidence interval CI 28–65 m). On univariable analysis for OS, the primary disease site, specifically the nape and neck (hazard ratio HR 3.3, 95% CI 1.4–7.7, p = 0.007), high Eastern Cooperative Oncology Group Performance Status (ECOG‐PS, HR 2.5, 95% CI = 1.9–3.3, p < 0.001), high lactate dehydrogenase (LDH) levels (HR 2.8, 95% CI = 1.7–4.6, p < 0.001), and treatment with targeted therapy (TT) as compared with immunotherapy (HR 2.6, 95% CI = 1.06–6.3, p = 0.03) were all associated with shorter OS. High‐grade adverse events (AEs) were associated with a longer OS (HR 0.41, 95% CI = 0.25–0.68, p = 0.001). On multivariable analysis for OS, the ECOG‐PS, LDH levels, site of disease, and the development of moderate‐severe AEs remained significant.
Conclusions
In the era of modern oncologic treatments, the prognosis of inoperable and metastatic cutaneous H&N melanoma aligns with other cutaneous melanomas. Primary tumor site of the nape and neck region emerges as a significant prognostic factor.
Level of Evidence
3 Laryngoscope, 134:2762–2770, 2024
Advanced cutaneous head and neck melanoma patients treated with systemic agents had a median overall survival of 45 m (95% confidence interval = 28–65). Site of primary disease is a significant prognostic factor, with nape and neck having the worst prognosis, while the face had the best prognosis. High Eastern Cooperative Oncology Group Performance Status, high lactate dehydrogenase, and targeted therapy (vs. immunotherapy) were associated with shorter survival.
Immunotherapy with anti–programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Recent data hint at better response to therapy for patients over age 65 years. ...Patients with metastatic melanoma in their 80's and 90's pose a clinical challenge. We describe a cohort of 144 patients ≥65 years and analyse the efficacy and toxicity of anti–PD-1 therapy in ages 80–100 years compared with ages 65–79 years. Records of metastatic melanoma patients aged 65–100 years treated with anti–PD-1 were collected retrospectively. Baseline parameters, response rate (overall response rate ORR), best response, progression-free survival (PFS) and overall survival (OS) and immune-related adverse events were analysed. Cox regression, t test, and chi-square test were used for statistical analysis. Five hundred patients were treated with anti–PD-1 agents between 2013 and 2018.Eighty-two patients were aged 65–79 years (group A, median 71.5 years), and 62 patients were aged 80–100 years (group B, median 84 years, range 80–97 years). Baseline parameters were comparable except for worse PS in group B (p = 0.001). One hundred twenty-four patients were evaluable for analysis of response (76 group A, 48 group B). A trend was noted for higher ORR in the older group with 62.3% for group A and 73.9% for group B (p = 0.09). Complete response was significantly higher in group B versus group A (47.9% versus 20%, p = 0.001). No significant difference was found in PFS or OS between the groups. Toxicity for all patients was similar at 22.8%–25.6% G2-4 adverse events. Elderly patients show enhanced response to anti–PD-1 therapy. Increasing age within the elderly patients group may predict an even better response to therapy and comparable survival in patients of very old age.
•Anti–programmed cell death-1 (PD-1) agents are very potent in elderly metastatic melanoma patients.•Very elderly metastatic melanoma patients older than 80 years are the most benefited.•Complete response rates in patients older than 80 years are close to 50%.•Tolerability of anti–PD-1 in elderly melanoma is similar to younger patients.
Clinical trials are an essential source for advances in oncologic care, yet the enrollment rate is only 2-4%. Patients' reluctance to participate is an important barrier. This study evaluates ...patients' level of understanding and attitudes towards clinical trials.
This cross-sectional study was conducted in the oncology department and day care unit at the oncology division Tel Aviv Sourasky Medical Center, Israel. From January 2015 to September 2016. Two-hundred patients' currently receiving active anti-cancer therapy at a large tertiary hospital completed an anonymous questionnaire comprised of demographic information, past experience in clinical research and basic knowledge on clinical trials.
The majority of respondents did not meet the minimum knowledge level criteria. In those who replied they would decline to participate in a clinical trial, concern were related to potential assignment to the placebo arm, provision of informed consent and trust issues with their oncologist. Those with sufficient knowledge were significantly more interested in participating. Patients with past experience in clinical trials had a higher level of academic education, were less religious, had a better understanding of medical research and were inclined to participate in future research.
Misperceptions of clinical trials may contribute substantially to the unwillingness to participate in them.
Aim: The selective BRAF and MEK inhibitors (BRAFi+MEKi) have substantially improved the survival of melanoma patients with BRAF V600 mutations. However, BRAFi+MEKi can also cause severe or fatal ...outcomes. We aimed to identify and compare serious adverse events (sAEs) that are significantly associated with BRAFi+MEKi. Methods: In this pharmacovigilance study, we reviewed FDA Adverse Event Reporting System (FAERS) data in order to detect sAE reporting in patients treated with the combination therapies vemurafenib+cobimetinib (V+C), dabrafenib+trametinib (D+T) and encorafenib+binimetinib (E+B). We evaluated the disproportionate reporting of BRAFi+MEKi-associated sAEs. Significant associations were further analyzed to identify combination-specific safety signals among BRAFi+MEKi. Results: From January 2018 through June 2019, we identified 11,721 sAE reports in patients receiving BRAFi+MEKi. Comparison of BRAFi+MEKi combinations demonstrates that skin toxicities, including Stevens–Johnson syndrome, were disproportionally reported using V+C, with an age-adjusted reporting odds ratio (adj. ROR) of 3.4 (95%CI, 2.9–4.0), whereas fever was most significantly associated with D+T treatment with an adj. ROR of 1.9 (95%CI, 1.5–2.4). Significant associations using E+B treatment include peripheral neuropathies (adj. ROR 2.7; 95%CI, 1.2–6.1) and renal disorders (adj. ROR 4.1; 95%CI, 1.3–12.5). Notably, we found an increase in the proportion of Guillain–Barré syndrome reports (adj. ROR 8.5; 95%CI, 2.1–35.0) in patients administered E+B. Conclusion: BRAFi+MEKi combinations share a similar safety profile attributed to class effects, yet concomitantly, these combinations display distinctive effects that can dramatically impact patients’ health. Owing to the limitations of pharmacovigilance studies, some findings warrant further validation. However, the possibility of an increased risk for these events should be considered in patient care.
Minimally invasive adrenalectomy has facilitated resection of resistant adrenal metastases. The adrenal gland may function as a sanctuary site for metastatic growth despite systemic therapy. The ...objective of the study was to assess the outcomes of selective minimally invasive adrenalectomy during immunotherapy.
Candidates included patients with adrenal metastases resistant to systemic therapy who underwent minimally invasive adrenalectomy.
There were 15 patients undergoing 16 minimally invasive adrenalectomies. Patients received either immunotherapy or BRAF inhibition prior to surgery. The mean operative time was 130 min with a median length of hospital stay of 2 days. At a median follow up of 24 months, 7 patients have no evidence of disease, 6 patients had progression with eventual mortality, while another patients has stable disease with maintenance therapy. One was lost to follow up.
Despite an increase in objective durable responses in metastatic melanoma, there is still some site-specific resistance in isolated areas like the adrenal where early minimally invasive adrenalectomy remains indicated.
•Minimally invasive adrenalectomy is indicated for resistant to therapy melanoma.•There can be site-specific resistance in isolated areas like the adrenal.•The adrenal gland may function as a sanctuary site for metastatic growth.
Despite an increase in objective durable response in metastatic melanoma to immunotherapies and targeted treatments, minimally invasive adrenalectomy offers advantage in adrenal disease resistant to medical therapy.
Immunotherapy has revolutionized the prognosis of patients with metastatic melanoma. To date, the most active regimen is the combination of ipilimumab + nivolumab (ipi-nivo) achieving a response rate ...of nearly 60% and a median survival (OS) of 6 years. However, approximately 40% of patients experience primary resistance, while around 50% experience secondary resistance, highlighting the need for an effective second-line treatment option The recently published results on the use of lenvatinib + pembrolizumab in the advanced line setting led to the adoption of this regimen at our institution. Here we present our experience with this regimen, focusing on efficacy and safety.
Electronic medical records of patients treated at a tertiary referral melanoma center, with at least one cycle of anti PD-1 + lenvatinib from 2020 to 2023 were analyzed for baseline demographic characteristics, disease related characteristics and treatment outcomes.
Forty-two patients were identified. The Response rate (RR) was 28% and the disease control rate was 38%. Responses were seen across different melanoma subtypes, including 67% in acral melanoma, 20% in uveal melanoma, and 25% in mucosal melanoma. Patients with a more aggressive disease manifested by elevated lactate dehydrogenase (LDH) achieved a RR of 26%, while patients with active central nervous system (CNS) metastases had a RR of 31%, and an intra-cranial RR of 23%. Responses were seen across lines of treatment, with a 25% RR in the second and third lines, and a 36% RR in the fourth and fifth lines. The median progression free survival was 3 months, and the median survival was 11 months. The treatment was not easily tolerated with 31% of the patients experiencing grade 3-4 toxicity, which was manageable through dose interruptions and reductions. Only 7% of patients discontinued the treatment due to toxicity.
Lenvatinib in combination with anti-PD1 had demonstrated both relative safety and efficacy in patients with metastatic melanoma of all subtypes in the advanced line setting. We are eagerly anticipating the mature results of the LEAP-004 study hoping that this regimen will receive regulatory approval, paving the way for its widespread adoption in daily practice worldwide.
Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has ...shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database—a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-naïve. The median follow-up was 12 months. The response rates for treatment-naïve and previously-treated patients were 61% and 25%, respectively; median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-naïve patients was 58% (95% CI 42–65). At data cutoff, 22% were still on-treatment. Grade 3–4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%); AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.
Background: Immunotherapy has revolutionized outcomes for melanoma patients, by significantly prolonging survival and probably even curing a fraction of metastatic patients. In daily practice, ...treatment for responding patients is often discontinued due to treatment-limiting toxicity, or electively, following a major tumor response. To date, the criteria for a safe stop and the optimal duration of treatment remain unclear. Patients and methods: This is a real-world single-site cohort of 106 advanced melanoma patients who were treated with immunotherapy and who discontinued treatments in the absence of disease progression. Here, we describe their long-term outcomes, and analyze the differential characteristics between patients who ultimately experienced progression and those who remained in unmaintained durable response. Results: Patients were treated with anti-PD-1 monotherapy (81%) or in combination with ipilimumab (19%) for a median of 15.2 m (range, 0.7–42.3 m). Upon discontinuation, 75.5% had achieved a complete response (CR). After a median follow-up of 20.8 m (range, 6–58) from discontinuation, 32% experienced disease progression. Median time to progression was 8.5 m (range, 1.5–37). Response to re-induction with anti-PD-1 was observed in 47%. On multivariate analysis, achieving a non-CR response, immunotherapy given in advanced line, and shorter treatment duration were significantly associated with lesser progression-free survival. Conclusions: This is one of the few reports on real-world melanoma patients who discontinued immunotherapy while responding to treatment. This study reveals the key factors to bear in mind when considering an elective treatment cessation. Specifically, patients with non-CR as best response and patients treated in an advanced-line setting should be treated for longer periods, and elective discontinuation should not take place prior to 18 m.
IMPORTANCE: In science and medical research, extreme and dichotomous conclusions may be drawn based on whether the P value falls above or below the threshold. The fragility index (ie, the minimum ...number of changes from nonevents to events resulting in loss of statistical significance) captures the vulnerability of statistics in trials with binary outcomes. There are a growing number of clinical trials of immune checkpoint inhibitors (ICIs), as well as expanding eligibility for patients to receive them. The robustness of survival outcomes in randomized clinical trials (RCTs) should be evaluated using the fragility index extended to time-to-event data. OBJECTIVE: To calculate the fragility of survival data in RCTs evaluating ICIs. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, data on phase 3 prospective RCTs investigating ICIs included in PubMed from inception until January 1, 2020, were extracted. Two- or three-group studies reporting results for overall survival were eligible for the survival-inferred fragility index (SIFI) calculation, which is the minimum number of reassignments of the best survivors from the interventional group to the control group resulting in loss of significance (defined as P < .05 by log-rank test). For nonsignificant results, a negative SIFI was calculated by reversing the direction of reassignment (from the control group to the interventional group). MAIN OUTCOMES AND MEASURES: Survival-inferred fragility index. RESULTS: A total of 45 phase 3 prospective RCTs (4 of which had 3 groups, for a total of 49 groups) were identified, of which 6 (13%) investigated anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) agents, 25 (56%) investigated anti–programmed cell death 1 (PD-1) agents, 12 (27%) investigated anti–programmed cell death 1 ligand 1 agents, and 3 (7%) investigated the combination of anti–CTLA-4 and anti–PD-1 agents. The median SIFI was 5 (interquartile range, –4 to 12) for the intention-to-treat analysis; for these trials, the SIFI was 1% or less of the total sample size in 17 of 49 populations (35%). In 25 of the 49 intention-to-treat populations (51%), the SIFI was less than the number of censored patients in the intervention group shortly after randomization (defined as <5% of the follow-up time). CONCLUSIONS AND RELEVANCE: This study suggests that many phase 3 RCTs evaluating ICI therapies have a low SIFI for overall survival, resulting in uncertainty regarding their potential clinical benefit. Although not a definitive solution for the problems arising from dichotomization, SIFI provides an additional means of assessing and communicating the strength of statistical conclusions.
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