An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors.

PURPOSE: Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection. METHODS: After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m2 was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry. RESULTS: Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log2 scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%. CONCLUSION: Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain. GOV IDENTIFIER: NCT02338037 (January 9, 2015).

Neoadjuvant intratumoral plasmid interleukin-12 electro-gene-transfer and nivolumab in patients with operable locoregionally advanced melanoma.

PURPOSE: Intratumoral (IT) TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of interleukin-12 (IL-12) within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous (IV) nivolumab followed by surgery and adjuvant nivolumab in patients with operable locoregionally advanced melanoma. PATIENTS AND METHODS: The neoadjuvant phase comprised up to 3 Χ 4-week cycles where TAVO-EP was given IT on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab IV on day 8 of each 4-week cycle. Surgery followed, and adjuvant nivolumab was initiated after surgery. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathological response (MPR; pCR or near pCR). RESULTS: Sixteen patients were enrolled and the preoperative radiological response rate was 63%. One patient declined surgery after experiencing a significant clinical response. Among the remaining 15 patients, pCR rate was 60% and MPR was 80%. No patient with MPR has had disease recurrence with a median follow-up from the date of surgery of 15.4 months. At baseline, most patients exhibited low CD8+ TIL, PD-L1 and IFN-γ gene expression signature. There was enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL and proliferating immune cell subsets. CONCLUSIONS: The clinical efficacy of neoadjuvant IT TAVO-EP + nivolumab is promising with 80% of patients achieving an MPR. Evidence of potent immune activation both systemically and within the TME along with a favorable safety profile supports the activity of local IL-12 and anti-PD1 based regimens.

Durability of response to immune checkpoint blockade following treatment discontinuation and efficacy of rechallenge in advanced Merkel cell carcinoma.

BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB) therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced patients with MCC who discontinued ICB treatment after achieving favorable initial response. METHODS: We performed a retrospective review of advanced patients with MCC treated at a single high-volume referral center, including all patients who received at least one dose of anti-programmed death receptor 1 (ligand) monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. RESULTS: Of 195 advanced patients with MCC treated with ICB, we identified 45 who met the study criteria. Of these, 21 (46.6%) had a complete response (CR) to initial ICB treatment, 23 (51.1%) a partial response and 1 (2.2%) SD. 25 (55.6%) patients discontinued ICB electively and 20 (44.4%) discontinued due to toxicity. In total, 21 of the 45 patients (46.6%) experienced disease progression at a median of 11.3 months (range 2.1-22.7 months) from ICB cessation. There was a lower rate of progression in patients who achieved CR versus non-CR (23.8% vs 66.7%, p=0.006) and a trend towards a lower rate in those who discontinued electively versus due to toxicity (36.0% vs 60.0%, p=0.14). There was a higher risk for progression in patients with viral positive MCC compared with viral negative MCC (75.0 vs 30.8%, p=0.02). 16 of the 21 patients who experienced progression were retreated subsequently with ICB therapy, including both single-agent rechallenge (12) and escalation to combination ICB (4). 11 of 15 evaluable ICB-retreated patients (73.3%) achieved an objective response. CONCLUSIONS: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICB response, particularly in those that achieve less than a CR. Most of these patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.

Performance of ChatGPT in classifying periodontitis according to the 2018 classification of periodontal diseases.

OBJECTIVES: This study assessed the ability of ChatGPT, an artificial intelligence(AI) language model, to determine the stage, grade, and extent of periodontitis based on the 2018 classification. MATERIALS AND METHODS: This study used baseline digital data of 200 untreated periodontitis patients to compare standardized reference diagnoses (RDs) with ChatGPT findings and determine the best criteria for assessing stage and grade. RDs were provided by four experts who examined each case. Standardized texts containing the relevant information for each situation were constructed to query ChatGPT. RDs were compared to ChatGPT's responses. Variables influencing the responses of ChatGPT were evaluated. RESULTS: ChatGPT successfully identified the periodontitis stage, grade, and extent in 59.5%, 50.5%, and 84.0% of cases, respectively. Cohen's kappa values for stage, grade and extent were respectively 0.447, 0.284, and 0.652. A multiple correspondence analysis showed high variance between ChatGPT's staging and the variables affecting the stage (64.08%) and low variance between ChatGPT's grading and the variables affecting the grade (42.71%). CONCLUSIONS: The present performance of ChatGPT in the classification of periodontitis exhibited a reasonable level. However, it is expected that additional improvements would increase its effectiveness and broaden its range of functionalities (NCT05926999). CLINICAL RELEVANCE: Despite ChatGPT's current limitations in accurately classifying periodontitis, it is important to note that the model has not been specifically trained for this task. However, it is expected that with additional improvements, the effectiveness and capabilities of ChatGPT might be enhanced.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

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.

Health-related quality of life in patients with metastatic basal cell carcinoma treated with cemiplimab: Analysis of a phase 2 trial.

BACKGROUND: A phase 2 cemiplimab study (NCT03132636) demonstrated a 24.1% objective response rate in patients diagnosed with metastatic basal cell carcinoma (mBCC) who were not candidates for continued hedgehog inhibitor (HHI) therapy due to intolerance to previous HHI therapy, disease progression while receiving HHI therapy, or having not better than stable disease on HHI therapy after 9 months. Here, health-related quality of life (QoL) for this patient population is reported. METHODS: Adult patients with mBCC were treated with intravenous cemiplimab at a dose of 350 mg every 3 weeks for 5 treatment cycles of 9 weeks/cycle then 4 treatment cycles of 12 weeks/cycle. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and Day 1 of each cycle. Across Cycles 2 to 9, the overall change from baseline was analyzed using a mixed model with repeated measures. Responder analyses determined clinically meaningful improvement or deterioration (changes ≥10 points) or maintenance across all scales. RESULTS: Patients reported low symptom burden and moderate-to-high functioning at baseline. Maintenance for QLQ-C30 global health status (GHS)/QoL and across all functioning and symptom scales was indicated by overall mean changes from baseline. Clinically meaningful improvement or maintenance was reported at Cycle 2 for GHS/QoL (77%), functioning scales (77% to 86%), and symptom scales (70% to 93%), with similar proportions of improvement or maintenance at Cycles 6 and 9, excluding fatigue. On the Skindex-16, clinically meaningful improvement or maintenance was reported across the emotional, symptom, and functional subscales, in 76%-88% of patients at Cycle 2, which were generally maintained at Cycles 6 and 9. Overall mean changes from baseline showed maintenance across these subscales. CONCLUSIONS: The majority of patients treated with cemiplimab reported improvement or maintenance in GHS/QoL and functioning while maintaining a low symptom burden.

Patient reported outcomes and patient experiences of immune checkpoint modulators for advanced or recurrent melanoma: a mixed methods study.

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.

First-in-Human Stage III/IV Melanoma Clinical Trial of Immune Priming Agent IFx-Hu2.0.

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.

Association of Peri-Implant Keratinized Mucosa Width and Mucosal Thickness with Early Bone Loss: A Cross-Sectional Study.

Objective: The objective of this study was to evaluate the effects of keratinized mucosa width (KMW) and mucosal thickness (MT) around dental implants on marginal bone loss (MBL). The evaluation was performed one year after loading by comparing clinical, radiographic, and biochemical parameters. Methods: The study included 87 implants in 87 patients undergoing regular follow-ups without hard or soft tissue augmentation one year after loading. Clinical measurements included plaque index (PI), gingival index (GI), bleeding on probing (BoP), probing depth (PD), KMW, and MT. MBL was assessed with periapical radiography. The peri-implant crevicular fluid (PICF) was analyzed for tumor necrosis factor-alpha (TNF-α), receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), and microRNA-27a. Results: The MBL of implants with thin MT (<2 mm) was higher than that of implants with thick MT (≥2 mm) (p < 0.05). A significant negative correlation (r: -0.217) was established between MT and MBL. No significant association was found between KMW and MBL (p > 0.05). No significant associations was found between KMW and MT with TNF-α, RANKL, OPG and RANKL/OPG (p > 0.05), with the exception of increased microRNA-27a levels in implants with KMW ≥ 2 mm (p < 0.05). Conclusions: Implants with a thick MT had a lower MBL. There may be an association between adequate KMW and high miRNA-27a levels. The relationship between MBL and miRNA-27a remains unclear.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

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.

Combined BRAF, MEK, and heat-shock protein 90 inhibition in advanced BRAF V600-mutant melanoma.

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.

Potential Use of ChatGPT for Patient Information in Periodontology: A Descriptive Pilot Study.

Objectives The aim of this study is to evaluate the accuracy and completeness of the answers given by Chat Generative Pre-trained Transformer (ChatGPT) (OpenAI OpCo, LLC, San Francisco, CA), to the most frequently asked questions on different topics in the field of periodontology. Methods The 10 most frequently asked questions by patients about seven different topics (periodontal diseases, peri-implant diseases, tooth sensitivity, gingival recessions, halitosis, dental implants, and periodontal surgery) in periodontology were created by ChatGPT. To obtain responses, a set of 70 questions was submitted to ChatGPT, with an allocation of 10 questions per subject. The responses that were documented were assessed using two distinct Likert scales by professionals specializing in the subject of periodontology. The accuracy of the responses was rated on a Likert scale ranging from one to six, while the completeness of the responses was rated on a scale ranging from one to three. Results The median accuracy score for all responses was six, while the completeness score was two. The mean scores for accuracy and completeness were 5.50 ± 0.23 and 2.34 ± 0.24, respectively. It was observed that ChatGPT's responses to the most frequently asked questions by patients for information purposes in periodontology were at least "nearly completely correct" in terms of accuracy and "adequate" in terms of completeness. There was a statistically significant difference between subjects in terms of accuracy and completeness (P<0.05). The highest and lowest accuracy scores were peri-implant diseases and gingival recession, respectively, while the highest and lowest completeness scores were gingival recession and dental implants, respectively. Conclusions The utilization of large language models has become increasingly prevalent, extending its applicability to patients within the healthcare domain. While ChatGPT may not offer absolute precision and comprehensive results without expert supervision, it is apparent that those within the field of periodontology can utilize it as an informational resource, albeit acknowledging the potential for inaccuracies.

Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial.

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 .

Cetuximab for Immunotherapy-Refractory/Ineligible Cutaneous Squamous Cell Carcinoma.

Anti-PD1 therapy demonstrated impressive, prolonged responses in advanced cutaneous squamous cell carcinoma (CSCC). Therapy for ICI-refractory/ineligible disease remains unclear. We performed a retrospective analysis in locally-advanced/metastatic CSCC using cetuximab across three cohorts: immediately after ICI failure (A), not immediately following ICI failure (B), or without prior ICI (C). The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), time-to-response (TTR) and toxicity. Twenty-three patients were included. In cohort A (n = 11), the ORR was 64% and DCR was 91%, with six ongoing responses at data cutoff. In cohort B (n = 2), all patients had progression as the best response. At a median follow-up of 21 months for A and B, TTR and PFS were 2.0 and 17.3 months, respectively. The median OS was not reached. In cohort C (n = 10), the ORR and DCR were 80%, including five ongoing responses at the data cutoff. At a median follow-up of 22.4 months, the TTR, PFS and OS were 2.5, 7.3 and 23.1 months, respectively. Cetuximab was well tolerated in all cohorts. In summary, cetuximab is effective in patients with failure/contraindications to ICI. Cetuximab immediately after ICI failure yielded particularly fast, durable responses. If confirmed, this could be the preferred therapy following ICI failure.

Efficacy of ipilimumab 3 mg/kg following progression on low-dose ipilimumab in metastatic melanoma.

BACKGROUND: Differing doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy. METHODS: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3± anti-PD1 antibody were eligible. Best investigator-determined Response Evaluation Criteria in Solid Tumours response, progression-free survival (PFS) and overall survival (OS) were analysed. RESULTS: Total 36 patients received low-dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting. Of which, 20 (56%) had primary resistance and 16 (44%) had acquired resistance. All patients received IPI3 for unresectable stage III or IV melanoma; median age 60 (29-78), 18 (50%) M1d disease, 32 (89%) Eastern Cooperative Oncology Group performance status 0-1. Around 35 (97%) received IPI3 with nivolumab and 1 received IPI3 alone. The response rate to IPI3 was 9/36 (25%). In patients with primary resistance, the response rate was 6/20 (30%). After a median follow-up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded; 1-year PFS and OS were 73% and 100%, respectively. CONCLUSIONS: IPI3 following recurrence/progression on low dose IPI has clinical activity, including in primary resistance. IPI dosing is therefore critical in a subset of patients.

Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. METHODS: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. RESULTS: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression. CONCLUSION: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.

Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.

BACKGROUND: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma who recur during or after adjuvant immunotherapy, including those that may or may not have undergone prior CLND. In this study, we aimed to answer this question. METHODS: Patients with resected stage III melanoma who received adjuvant anti-programmed cell death protein-1 (PD-1) (±ipilimumab) immunotherapy with a subsequent locoregional (lymph node and/or in-transit metastases) recurrence were retrospectively identified. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was rate of subsequent locoregional recurrence; secondary outcomes were locoregional recurrence-free survival (lr-RFS2) and overall RFS (RFS2) to second recurrence. RESULTS: In total, 71 patients were identified: 42 (59%) men, 30 (42%) BRAF V600E mutant, 43 (61%) stage IIIC at diagnosis. Median time to first recurrence was 7 months (1-44), 24 (34%) received adjuvant RT and 47 (66%) did not. Thirty-three patients (46%) developed a second recurrence at a median of 5 months (1-22). The rate of locoregional relapse at second recurrence was lower in those who received adjuvant RT (8%, 2/24) compared with those who did not (36%, 17/47, p=0.01). Adjuvant RT at first recurrence was associated with an improved lr-RFS2 (HR 0.16, p=0.015), with a trend towards an improved RFS2 (HR 0.54, p=0.072) and no effect on risk of distant recurrence or overall survival. CONCLUSION: This is the first study to investigate the role of adjuvant RT in patients with melanoma with locoregional disease recurrence during or after adjuvant anti-PD-1-based immunotherapy. Adjuvant RT was associated with improved lr-RFS2, but not risk of distant recurrence, demonstrating a likely benefit in locoregional disease control in the modern era. Further prospective studies are required to validate these results.

Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma.

BACKGROUND: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER: NCT01176474 and NCT02970981.

Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study.

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment. RESULTS: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. CONCLUSIONS: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.