Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis.

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Deletion of the auxiliary α2δ1 voltage sensitive calcium channel subunit in osteocytes and late-stage osteoblasts impairs femur strength and load-induced bone formation in male mice.

Osteocytes sense and respond to mechanical force by controlling the activity of other bone cells. However, the mechanisms by which osteocytes sense mechanical input and transmit biological signals remain unclear. Voltage-sensitive calcium channels (VSCCs) regulate calcium (Ca2+) influx in response to external stimuli. Inhibition or deletion of VSCCs impairs osteogenesis and skeletal responses to mechanical loading. VSCC activity is influenced by its auxiliary subunits, which bind the channel's α1 pore-forming subunit to alter intracellular Ca2+ concentrations. The α2δ1 auxiliary subunit associates with the pore-forming subunit via a glycosylphosphatidylinositol anchor and regulates the channel's calcium-gating kinetics. Knockdown of α2δ1 in osteocytes impairs responses to membrane stretch, and global deletion of α2δ1 in mice results in osteopenia and impaired skeletal responses to loading in vivo. Therefore, we hypothesized that the α2δ1 subunit functions as a mechanotransducer, and its deletion in osteocytes would impair skeletal development and load-induced bone formation. Mice (C57BL/6) with LoxP sequences flanking Cacna2d1, the gene encoding α2δ1, were crossed with mice expressing Cre under the control of the Dmp1 promoter (10 kb). Deletion of α2δ1 in osteocytes and late-stage osteoblasts decreased femoral bone quantity (P < .05) by DXA, reduced relative osteoid surface (P < .05), and altered osteoblast and osteocyte regulatory gene expression (P < .01). Cacna2d1f/f, Cre + male mice displayed decreased femoral strength and lower 10-wk cancellous bone in vivo micro-computed tomography measurements at the proximal tibia (P < .01) compared to controls, whereas Cacna2d1f/f, Cre + female mice showed impaired 20-wk cancellous and cortical bone ex vivo micro-computed tomography measurements (P < .05) vs controls. Deletion of α2δ1 in osteocytes and late-stage osteoblasts suppressed load-induced calcium signaling in vivo and decreased anabolic responses to mechanical loading in male mice, demonstrating decreased mechanosensitivity. Collectively, the α2δ1 auxiliary subunit is essential for the regulation of osteoid-formation, femur strength, and load-induced bone formation in male mice.

The ability of bone to sense and respond to forces generated during daily physical activities is essential to skeletal health. Although several bone cell types contribute to the maintenance of bone health, osteocytes are thought to be the primary mechanosensitive cells; however, the mechanisms through which these cells perceive mechanical stimuli remains unclear. Previous work has shown that voltage sensitive calcium channels are necessary for bone to sense mechanical force; yet the means by which those channels translate the physical signal into a biochemical signal is unclear. Data within this manuscript demonstrate that the extracellular α2δ1 subunit of voltage sensitive calcium channels is necessary for load-induced bone formation as well as to enable calcium influx within osteocytes. As this subunit enables physical interactions of the channel pore with the extracellular matrix, our data demonstrate the need for the α2δ1 subunit for mechanically induced bone adaptation, thus serving as a physical conduit through which mechanical signals from the bone matrix are transduced into biochemical signals by enabling calcium influx into osteocytes.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Intravital imaging of osteocyte integrin dynamics with locally injectable fluorescent nanoparticles.

Osteocytes are the resident mechanosensory cells in bone. They are responsible for skeletal homeostasis and adaptation to mechanical cues. Integrin proteins play a prominent role in osteocyte mechanotransduction, but the details are not well stratified. Intravital imaging with multiphoton microscopy presents an opportunity to study molecular level mechanobiological events in vivo and presents an opportunity to study integrin dynamics in osteocytes. However, fluorescent imaging limitations with respect to excessive optical scattering and low signal to noise ratio caused by mineralized bone matrix make such investigations non-trivial. Here, we demonstrate that ultra-small and bright fluorescent core-shell silica nanoparticles (<7 nm diameter), known as Cornell Prime Dots (C'Dots), are well-suited for the in vivo bone microenvironment and can improve intravital imaging capabilities. We report validation studies for C'Dots as a novel, locally injectable in vivo osteocyte imaging tool for both non-specific cellular uptake and for targeting integrins. The pharmacokinetics of C'Dots reveal distinct sex differences in nanoparticle intracellular dynamics and clearance in osteocytes, which represents a novel topic of study in bone biology. Integrin-targeted C'Dots were used to study osteocyte integrin dynamics. To the best of our knowledge, we report here the first evidence of osteocyte integrin endocytosis and recycling in vivo. Our results provide novel insights in osteocyte biology and will open up new lines of investigation that were previously unavailable in vivo.

Post or perish? Social media strategies for disseminating orthopedic research.

Social media usage, particularly Twitter, among scientists in academia has increased in recent years. However, Twitter's use in scholarly post-publication dissemination of orthopaedic research and musculoskeletal advocacy remains low. To enhance usage of Twitter among musculoskeletal researchers, this article reviews data supporting the professional benefits of using the platform to disseminate scholarly works. Next, we provide a linear workflow for Tweet curation, discuss the importance of data-driven decision making behind tweet curation and posting, and propose new guidelines for professional Twitter usage. Since this workflow may not eliminate all the identified barriers and new institutionalized shifts in policies regarding curation and consumption of social media on Twitter, we also briefly introduce and explore using other social media platforms. We hope this information will be persuasive and compelling to those in the orthopedic research field and be broadly applicable to others in related scientific fields who wish to disseminate findings and engage a public audience on social media. In addition, we encourage the Orthopedic Research Society (ORS) and Journal of Orthopedic Research (JOR) communities to take advantage of the many tools curated by the Wiley editorial office and the ORS social media committee to increase dissemination of their scholarly works online. Twitter and social media can assist in accomplishing our mission of creating a world without musculoskeletal limitations via the timely dissemination of orthopedic information. However, this can only be accomplished if the orthopedic research community has a unified and strong online presence actively engaged in orthopaedic research findings and news.

A Fluorescent Intravital Imaging Approach to Study Load-Induced Calcium Signaling Dynamics in Mouse Osteocytes.

Bone tissue is exquisitely sensitive to differences in mechanical load magnitude. Osteocytes, dendritic cells that form a syncytium throughout the bone, are responsible for the mechanosensory function of bone tissue. Studies employing histology, mathematical modeling, cell culture, and ex vivo bone organ cultures have greatly advanced the understanding of osteocyte mechanobiology. However, the fundamental question of how osteocytes respond to and encode mechanical information at the molecular level in vivo is not well understood. Intracellular calcium concentration fluctuations in osteocytes offer a useful target for learning more about acute bone mechanotransduction mechanisms. Here, we report a method for studying osteocyte mechanobiology in vivo, combining a mouse strain with a fluorescently genetically encoded calcium indicator expressed in osteocytes with an in vivo loading and imaging system to directly detect osteocyte calcium levels during loading. This is achieved with a three-point bending device that can deliver well-defined mechanical loads to the third metatarsal of living mice while simultaneously monitoring fluorescently indicated calcium responses of osteocytes using two-photon microscopy. This technique allows for direct in vivo observation of osteocyte calcium signaling events in response to whole bone loading and is useful in the endeavor to reveal mechanisms in osteocyte mechanobiology.

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

BACKGROUND: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. METHODS: The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. INTERPRETATION: Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAFV600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. FUNDING: F Hoffmann-La Roche.

Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial.

Importance: A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL). Objective: To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI). Design, Setting, and Participants: The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QOL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QOL end point. Interventions: Patients were randomized (1:1) to treatment with adjuvant pembrolizumab vs standard of care with ipilimumab/HDI. Main Outcomes and Measures: Quality of life was assessed for patients at baseline and cycles 1, 3, 5, 7, and 9 after randomization using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy-Diarrhea, and European QOL 5-Dimension 3-Level scales. The primary end point was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate QOL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and programmed cell death ligand 1 status. A clinically meaningful difference of 5 points was targeted. Results: Among 1303 eligible patients (median [range] age, 56.7 [18.3-86.0] years; 524 women [40.2%]; 779 men [59.8%]; 10 Asian [0.8%], 7 Black [0.5%], 44 Hispanic [3.4%], and 1243 White [95.4%] individuals), 1188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3 (ipilimumab/HDI = 267 [32.1%]; pembrolizumab = 565 [67.9%]). Evaluable patients were predominantly younger than 65 years (623 [74.9%]) and male (779 [58.9%]). Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% CI, 7.9-11.3; P < .001) higher (better QOL) for pembrolizumab compared with ipilimumab/HDI, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favor of pembrolizumab through cycle 7. In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8; P < .001) or HDI (difference, 17.0 points; 95% CI, 14.6-19.4; P < .001). Conclusions and Relevance: This secondary analysis of a phase 3 randomized clinical trial found that adjuvant pembrolizumab improved QOL vs treatment with adjuvant ipilimumab or HDI in patients with high-risk resected melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT02506153.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP.

Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study.

BACKGROUND: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. METHODS: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study.

PURPOSE: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. RESULTS: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%). CONCLUSIONS: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.

PIVOT-12: a phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence.

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence. Clinical Trial Registration: NCT04410445 (ClinicalTrials.gov).

Brief overview: cemiplimab for the treatment of advanced basal cell carcinoma: PD-1 strikes again.

Basal cell carcinoma (BCC) is the most common malignancy worldwide. Fortunately, most tumors are localized and easily amenable to surgical resection or locally destructive treatments. However, a subset of BCCs can become locally advanced or metastatic. The development of small-molecule inhibitors of smoothened, a protein in the hedgehog pathway, which is almost universally activated in BCCs, was a breakthrough in the treatment of patients with advanced BCC. However, these agents are associated with primary and secondary resistance and have a toxicity profile that makes long-term use difficult. The recent approval of cemiplimab for patients with advanced BCC who are resistant to or are intolerant of hedgehog inhibitor therapy fills a significant unmet need as these patients now have a viable, second-line systemic therapeutic option. This article summarizes the rationale and data leading to the approval for cemiplimab in advanced BCC.

Adjuvant Therapy for Stage III Melanoma Without Immediate Completion Lymph Node Dissection.

INTRODUCTION: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND. METHODS: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively. Nodal recurrence, recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival were evaluated. RESULTS: Among 90 patients, 56 (62%) received adjuvant therapy and 34 (38%) underwent observation alone. Patients who received adjuvant therapy were younger (mean age: 53 vs. 65, p < 0.001) and had higher overall stage (Stage IIIb/c 75% vs. 54%, p = 0.041). Disease recurred in 12 of 34 patients (35%) in the observation group and 11 of 56 patients (20%) in the adjuvant therapy group. The most common first site of recurrence was distant recurrence alone (5/34 patients) in the observation group and nodal recurrence alone (8/90 patients) in the adjuvant therapy group. Despite more adverse nodal features in the adjuvant therapy group, 24-month nodal recurrence rate and RFS were not significantly different between the adjuvant and observation cohorts (nodal recurrence rate: 26% vs. 20%, p = 0.68; RFS: 75% vs. 61%, p = 0.39). Among patients with stage IIIb/c disease, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%, p = 0.04). CONCLUSIONS: In this early report, modern adjuvant therapy in patients who forego CLND is associated with longer DMFS among patients with stage IIIb/c disease.

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. SIGNIFICANCE: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study.

BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD