bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and genomic landscape of EGFR-mutant lung cancers (LCs) with squamous and adenosquamous differentiation.
Authors: Elkrief Arielle , Falcon Christina J. , Richards Allison L. , Dymun Alexandria , Paik Paul K. , Aly Rania G. , Rekhtman Natasha , Rudin Charles M. , Quintanal-Villalonga Alvaro , Yu Helena Alexandra
Published: June 2023

9129

Background: Outcomes to first-line therapy with osimertinib in patients (pts) with EGFR-mutant (EGFR+) squamous (sq) or adenosquamous (adenosq) LC have not been well described. Pts also undergo adenocarcinoma to squamous transformation (transformed) after treatment with EGFR tyrosine kinase inhibitor (TKI). The clinical and genomic characteristics of pts with EGFR+ sq and adenosq LC are largely unknown. Methods: We clinically and genomically characterized all pts with EGFR+ LC with baseline sq or adenosq histology and transformed histology at Memorial Sloan Kettering Cancer Center. Next-generation sequencing was performed with the MSK-IMPACT. We compared clinical outcomes (time to discontinuation (TTD), overall survival (OS), and post-progression survival after osimertinib discontinuation (PPS)) among the different cohorts. Results: A total of 51 pts were identified: 14 with baseline sq/adenosq treated with first-line (1L) osimertinib; 8 transformed cases post 1L osimertinib; 13 with baseline sq/adenosq treated with early generation TKI; 3 transformed cases post early generation TKI; the remainder of pts had early-stage EGFR+LC with baseline sq/adenosq. Median age was 63, and 57% were female. Eighteen (35%) were former or current smokers. Among pts with baseline sq/adenosq histology who were treated with 1L osimertinib, median TTD was 11.1 months (95%CI 7.7, not reached (NR)), and median OS was 24.3 months (95%CI 11.1 months, NR). Compared to a non-overlapping time-matched cohort with baseline adenocarcinoma treated with 1L osimertinib (N = 55), TTD was numerically shorter in the sq/adenosq cohort (11 vs. 17 months, HR 1.8, p = 0.076), and median OS was significantly shorter (24 vs. 33 months, HR 2.64, p = 0.03). PPS was shortest in baseline sq/adenosq (5 months, HR 2.94, p = 0.023), but similar in transformed (11 months, HR 0.89, p = 0.8) compared to adeno (11 months). The sq/adenosq cohort had significantly higher proportion of L858R EGFR (48% vs 31% p < 0.001) and atypical EGFR mutations at baseline (17% vs 7.3%, p < 0.001) compared to the adenocarcinoma cohort. PIK3CA mutations were enriched at baseline in the sq/adenosq cohort. In the transformed cases, RB1 alterations were present in 13% at baseline. There was a similar distribution of type of EGFR mutations in the non-overlapping pts in the AACR GENIE EGFR+ LC cohort with sq/adenosq histology (N = 4, 50% L858R, 25% atypical). Conclusions: Pts with EGFR+ sq/adenosq LCs exhibit inferior TTD and OS with 1L osimertinib compared to adenocarcinoma controls. Sq/adenosq LCs appear to be molecularly distinct with enrichment in EGFR L858R and atypical EGFR mutations. Transcriptomic profiling of a subset of samples will be presented. Our findings highlight the need for novel therapeutic strategies among pts in this high-risk subgroup.
Artificial intelligence algorithm developed to predict immune checkpoint inhibitors efficacy in non–small-cell lung cancer.
Authors: Rakaee Mehrdad , Tafavvoghi Masoud , Adib Elio , Ricciuti Biagio , Alessi Joao Victor Machado , Cortellini Alessio , Fulgenzi Claudia A.M. , Møllersen Kajsa , Bongo Lars Ailo , Hashemi Sayed MS , Houda Ilias , Busund Lill-Tove Rasmussen , Donnem Tom , Bahce Idris , Pinato David J. James , Sholl Lynette M. , Awad Mark M. , Kwiatkowski David J.
Published: June 2023

9132

Background: Many non-small cell lung cancer (NSCLC) patients with high PD-L1 IHC expression and/or high TMB level do not respond to immune-check point inhibitors (ICIs). Discovery of novel predictive biomarkers for ICI response in NSCLC continues to be a critical unmet medical need, given the expense, potential toxicity, and therapeutic delay due to ICI treatment without benefit. Methods: We developed a supervised deep learning algorithm (Deep-IO) to predict therapeutic response to ICIs in NSCLC patients from standard histology whole slide hematoxylin and eosin (H&E) images, which was trained based on ICI objective response rate. We utilized a convolutional neural network (CNN) implemented in Pytorch. The efficiency of the Deep-IO was evaluated through classification performance metrics and the area under the receiver operating characteristic curve (AUROC). The algorithm was trained and tested on 85218 tiles (size: 512x512 pixels) in 446 advanced stage NSCLC patients from the Dana Farber Cancer Institute (DFCI), all treated with ICI monotherapy. Results: The objective response rate, comprising complete and partial response, was 26% (n = 114) in the overall cohort. The DFCI patient cohort was randomly split into a training set (N=379, 85%) and a test set (N=67, 15%). The classifier’s predicted class (responder vs non-responder) probabilities at the tiles level were averaged for each patient. Quantitative evaluation of whole section test dataset shows that the developed model achieves the accuracy of 0.72, weighted average (WAVG) precision of 0.77, WAVG recall of 0.72 and WAVG F-score of 0.74 on classifying ICI non-responders from responders. Comparing with PD-L1 expression (TPS%) and TMB (mu/Mb), Deep-IO had superior predictive power for ICI response (AUROC=0.75) in the test set. The combined Deep-IO+PD-L1 scores resulted in a significantly greater AUROC value of 0.82 compared to single tests and a 32% improvement in specificity (0.88 vs. 0.56) compared to PD-L1 evaluation alone (Table). Conclusions: This proof-of-concept study shows that an artificial intelligence–powered H&E image classifier can predict ICI effectiveness in NSCLC. Deep-IO outperformed both established predictive biomarkers. We will assess Deep-IO in additional external NSCLC data sets for validation and confirmation. [Table: see text]
Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047.
Authors: Tawbi Hussein A. , Hodi F. Stephen , Lipson Evan J. , Schadendorf Dirk , Ascierto Paolo Antonio , Matamala Luis , Gutiérrez Erika Castillo , Rutkowski Piotr , Gogas Helen , Lao Christopher D. , Janoski De Menezes Juliana , Dalle Stéphane , Arance Ana Maria , Grob Jean-Jacques , Ratto Barbara , Rodriguez Saima , Xu Yuanfang , Dolfi Sonia , Long Georgina V.
Published: June 2023

9502

Background: In RELATIVITY-047 (NCT03470922), NIVO + RELA demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO; there was an observed improvement in overall survival (OS) although it was not statistically significant. The combination also had a descriptively higher confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) vs NIVO. Here we report updated descriptive analyses (efficacy, safety, and secondary analyses) with longer (~ 2 years) follow-up. Methods: Patients were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg fixed-dose combination or NIVO 480 mg every 4 weeks, as previously described. Primary endpoint of PFS per RECIST v1.1 was assessed by BICR; secondary endpoints included OS and ORR per BICR. Exploratory analyses were performed for melanoma-specific survival (MSS; defined as death due to melanoma, with censoring of deaths due to other causes) and efficacy outcomes on subsequent systemic therapy. Results: Patients received NIVO + RELA (n = 355) or NIVO (n = 359). Median follow-up was 25.3 months in this updated analysis (minimum follow-up, 21.0 months). NIVO + RELA continued to show a benefit over NIVO for PFS, OS and ORR (Table). A similar improvement was also observed in MSS. NIVO + RELA was generally favored over NIVO across key subgroups (consistent with previous reports). Subsequent systemic therapy was received by 131 (36.9%) and 136 (37.9%) patients in the NIVO + RELA and NIVO arms, respectively. Treatment-related adverse events (TRAEs; any grade) leading to treatment discontinuation were observed in 61 (17.2%) and 31 (8.6%) patients on NIVO + RELA and NIVO, respectively. Grade 3–4 TRAEs were observed in 78 (22.0%) patients on NIVO + RELA and 43 (12.0%) patients on NIVO. In total, there were 6 treatment-related deaths (NIVO + RELA, n = 4; NIVO, n = 2); no new treatment-related deaths have been reported since the last analysis. Conclusions: With 12.3 months of additional follow-up, a consistent benefit was observed with NIVO + RELA vs NIVO for PFS, OS and ORR in the ITT population, as well as in key patient subgroups. MSS was longer with NIVO + RELA compared with NIVO. The safety profile of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. Efficacy outcomes on subsequent systemic therapy (by type of subsequent therapy, including PD-L1/CTLA-4) will be presented. Clinical trial information: NCT03470922 . [Table: see text]
Association of biomarkers (BMs) with efficacy of adjuvant nivolumab (NIVO) vs placebo (PBO) in patients with resected stage IIB/C melanoma (CA209-76K).
Authors: Long Georgina V. , Kirkwood John M. M. , Hoeller Christoph , Grob Jean-Jacques , Weber Jeffrey S. , Taube Janis M. , Mohr Peter , Van Akkooi Alexander Christopher Jonathan , Loquai Carmen , Dutriaux Caroline , Chiarion-Sileni Vanna , Tenney Daniel J. , Dolfi Sonia , Tang Hao , Ritchings Corey , Lobo Maurice , Campigotto Federico , Wang Wenjia , Gastman Brian , Del Vecchio Michele
Published: June 2023

9504

Background: Adjuvant NIVO significantly prolonged recurrence-free survival (RFS) over PBO in stage IIB/C melanoma in the randomized, phase III Checkmate 76K trial (HR; 95% CI: 0.42 [0.30–0.59]). For the first time, select BMs and their association with RFS were analyzed in early-stage melanoma treated with an anti-PD-1 agent. Methods: Baseline primary tumor and serum BMs were analyzed, including interferon gamma-related gene expression signature (IFNγ-sig), TMB, BRAF mutation, % intratumoral CD8+ T cells, tumor cell PD-L1 expression, and serum CRP levels. BMs were evaluated as continuous variables (high vs low levels) and dichotomized by median or prespecified cutoffs. HRs were estimated using a Cox proportional hazards model. Results: Analysis of continuous BM levels within treatment arms showed that higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with prolonged RFS with NIVO but not PBO. The same trend was observed in the dichotomized analyses. No clear association between PD-L1 expression and RFS was identified in either arm. Benefit of NIVO over PBO was seen across all BM subgroups, including by BRAFV600 mutation status. Patients with higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels showed numerically greater relative benefit with NIVO, although CIs overlapped (Table). Conclusions: Higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with longer RFS with NIVO treatment. No BMs assessed were prognostic for RFS in the PBO arm, in contrast to previous reports in melanoma. Prolonged RFS was seen in patients treated with NIVO over PBO across levels of BMs, and irrespective of BRAF mutational status. Composite analyses of BMs with clinical and histopathologic factors will be evaluated for their potential to optimize risk:benefit stratification for NIVO in this patient population. Clinical trial information: NCT04099251 . [Table: see text]
Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.
Authors: Si Lu , Zou Zhengyun , Zhang Weizhen , Fang Meiyu , Zhang Xiaoshi , Luo Zhiguo , Chen Jing , Huang Gang , Zhang Peng , Cheng Ying , Liu Jiwei , Liu Jiyan , Zhang Junping , Wu Di , Chen Yu , Ma Xiaobiao , Wei Xiaoting , Sun Peng , Jia Zhongwei , Guo Jun
Published: June 2023

9510

Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .
Revisiting the optimal neoadjuvant immunotherapy regimen in resectable stage III melanoma based on the interferon gamma signature: A pooled analysis.
Authors: Lucas Minke W. , Dimitriadis Petros , Reijers Irene L.M. , Menzies Alexander M. , Rozeman Elisa A. , Versluis Judith M. , Huang Alexander Chan Chi , Cornelissen Sten , Broeks Annegien , Scolyer Richard A. , Mitchell Tara C. , Long Georgina V. , Blank Christian U.
Published: June 2023

9516

Background: Neoadjuvant anti-PD1 has been shown to be superior to adjuvant administration. Combination of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) induces even higher pathologic response rates (pRR) and event-free survival (EFS), but at the cost of higher toxicity. We previously showed that the interferon gamma (IFN-γ) signature is associated with a higher pRR after neoadjuvant IPI+NIVO. We hypothesized that IFN-γ high patients (pts) might benefit from less toxic anti-PD1 monotherapy (mono), while IFN-γ low pts might need an escalated regimen with IPI 3mg/kg + NIVO 1mg/kg. Methods: In this pooled analysis, pts with macroscopic nodal melanoma who received neoadjuvant NIVO 1mg/kg + IPI 3mg/kg (IPI3/NIVO1), IPI 1mg/kg + NIVO 3mg/kg (IPI1/NIVO3), sequential IPI 3mg/kg and NIVO 3mg/kg (IPI3>NIVO3), or NIVO mono (240mg; IFN-γ high pts only) from the OpACIN-neo, PRADO and DONIMI trials, were analyzed according to their baseline IFN-γ signature. RNA gene expression from baseline tumor biopsies was analyzed using the Nanostring nCounter platform. The IFN-γ scores were calculated using an algorithm and cut-off previously developed at the NKI and prospectively tested in the DONIMI trial. Results: Baseline tumor material was available from 151 pts (Table). Median follow-up was 42 months for the entire cohort and 19 months for NIVO mono pts. Combined IPI+NIVO in IFN-γ high pts induced similar major pathologic response (MPR) rates compared to NIVO mono in IFN-γ high pts (71% vs 80%, p=0.715), and significantly higher MPR rates compared to IPI+NIVO in IFN-γ low pts (71% vs 45%, p=0.003). At 18-months, EFS rates were 87%, 100% and 73% respectively, and overall survival (OS) rates were 98%, 100% and 96%. Notably, IPI3/NIVO1 seemed to induce a higher MPR rate than IPI1/NIVO3 in IFN-γ low pts (64% vs 41%), which was not statistically significant due to small subgroups. At 36 months, EFS was 91% vs 62% and OS was 91% vs 82%. Conclusions: Neoadjuvant NIVO mono seems to have equal outcomes as IPI+NIVO in IFN-γ high pts. IFN-γ low pts may benefit from IPI+NIVO with higher doses of IPI. Incorporating baseline biomarkers like the IFN-γ signature algorithm in neoadjuvant treatment decisions will optimize the risk-benefit ratio for these pts. [Table: see text]
Efficacy of adjuvant therapy in patients (pts) with AJCC v8 stage IIIA cutaneous melanoma.
Authors: Grover Piyush , Li Isabel , Kuijpers Anke , Kreidieh Firas Y. , Williamson Andrew , Amaral Teresa Maria Santos , Dimitriou Florentia , Placzke Joanna , Olino Kelly , Vitale Maria Grazia , Saiag Philippe , Gutzmer Ralf , Allayous Clara , Olofsson Bagge Roger , Asher Nethanel , Meniawy Tarek , Lawless Aleigha , Warburton Lydia , Menzies Alexander M. , Long Georgina V.
Published: June 2023

9518

Background: Pts with resected AJCC v8 stage IIIA melanoma have been under-represented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted and immunotherapy in this population is unclear. Methods: In this multicenter, retrospective study, pts with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab (PD1), BRAF/MEK-targeted therapy dabrafenib + trametinib (TT), or no adjuvant treatment (OBS) were included. Recurrence free survival (RFS), distant metastasis free survival (DMFS), and toxicity rates were examined. Results: 613 pts from 34 centers across Australia, Europe and USA were included. The median follow-up was 2.6 yrs (IQR, 1.6-3.4 yrs). Pt characteristics and follow-up were similar across the cohorts (Table). Completion rates of 12-month PD1 and TT therapy were 57.0% and 69.2% respectively. 1-yr RFS was 93.3% (95% CI, 90.3-96.4) in PD1, 100% in TT and 91.3% (95% CI, 88.1-94.7) in OBS cohorts. 2-yr RFS was 79.3% (95% CI, 74.1-84.8) for PD1, 100% for TT and 84.3% (95% CI, 79.9-89.0) in OBS cohorts. 2-yr DMFS was 88.4% (95% CI, 84.3-92.8) in PD1, 100% in TT and 91.1% (95% CI, 87.7-94.7) in OBS cohorts. Risk of recurrence was associated with higher breslow thickness (HR 1.73, 95% CI 1.36-2.20), higher mitotic rate (HR 1.07, 95% CI 1.02-1.12) and neck as the site of nodal metastases (HR 2.71, 95% CI 1.45-5.06) in the overall cohort (p<0.05). Neck nodal metastases were associated with higher risk of recurrence in OBS cohort (HR 3.82, 95% CI 1.91-7.66; p<0.05) but not in the PD1 cohort. Rates of ≥ Grade 3 toxicities were 10.9% with PD1 and 20.0% with TT; discontinuation due to toxicity occurred in 25.0% and 30.0%, respectively. No new safety signals were observed. Rates of unresolved toxicity at last follow-up were 26.9% in PD1 and 7.7% in TT cohorts. Conclusions: In this large international study, adjuvant PD1 or TT did not significantly improve RFS or DMFS compared to OBS in pts with resected stage IIIA melanoma. Prognosis in stage IIIA melanoma is favourable and outcomes after adjuvant therapy in this population needs further study in prospective randomised trials. [Table: see text]
Identification of RPTOR mutation as a novel predictor of efficacious immunotherapy in melanoma.
Authors: Li Yongzhao , Zhang Qin , Tan Yuan , Duan Qianqian , Sun Tingting , Qi Chuang
Published: June 2023

9524

Background: mTOR pathway is known to influence cancer immunity by metabolism reprogramming. RPTOR (Regulatory Associated Protein of MTOR Complex 1), one of mTOR pathway genes, which is involving in control of mammalian target of mTORC1 activity for regulating cell growth and survival. Whether mutations of RPTOR are associated with clinical efficacy of immune checkpoint inhibitors (ICIs) in melanoma is still ambiguous. Methods: In discovery cohort, we retrospective analyzed the genomic data of 418 melanoma samples which derived from seven immunotherapy studies ( http://www.cbioportal.org/ ) to evaluate the relationship between RPTOR mutation status and efficacy of immunotherapy. Then in validation cohort, the predictive value of RPTOR mutation was confirmed in 320 melanomas from MSKCC cohort (http://www.cbioportal.org/). TMB was calculated as the total count of nonsynonymous mutations in coding sequence. We used the CIBERSORT to evaluate the 22 types immune cell infiltration status in TCGA melanoma cohort. Results: The TMB level of RPTOR-mutant patients was higher than RPTOR-wildtype patients in both discovery (Median [IQR]: 43.11[23.76-140.15] vs. 6.13[2.07-13.66], P < 0.001) and validation (Median [IQR]: 37.38[20.17-84.95] vs. 8.85[3.35-21.07], P < 0.001) cohort. In discovery cohort, compared to RPTOR-wildtype patients, the RPTOR-mutant patients achieved prolonged OS (median OS: not reach, NR vs 22.7 months, HR (95%CI): 0.47(0.22-0.99), P = 0.043). This result was confirmed in validation cohort (median OS: NR vs. 42; HR (95%CI): 0.34 (0.11-1.0); P = 0.049). According to analysis of immune cell infiltration status, the mechanism of the predictive values of RPTOR mutations to ICI efficacy may be activated CD4 memory T cell more abundant in RPTOR-mutant tumors. Conclusions: RPTOR mutation is associated with higher TMB in ICI-treated melanoma patients. Survival analysis shows RPTOR mutation have a good link with longer OS after immunotherapy. These findings indicate that RPTOR mutation may serve as a potential predictive biomarker for ICIs in melanoma.
Encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for unresectable locally advanced or metastatic BRAF V600-mutant melanoma: Results from STARBOARD safety lead-in (SLI).
Authors: Schadendorf Dirk , Dummer Reinhard , Robert Caroline , Ribas Antoni , Sullivan Ryan J. , Panella Timothy J. , McKean Meredith , Santos Edgardo S. , Clancy Jill S. , Thakur Mahgull Nazar , Polli Anna , Di Pietro Alessandra , Ascierto Paolo Antonio
Published: June 2023

9531

Background: BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi) (eg, enco + bini) and immune checkpoint inhibitors (CPIs) (eg, pembro) are approved for patients (pts) with BRAF V600-mutant metastatic melanoma. Combinations of BRAFi + MEKi with CPIs further improve outcomes and may offer additional treatment strategies. STARBOARD (NCT04657991) is an ongoing randomized, double-blinded, placebo-controlled, phase 3 study of enco + bini + pembro vs pembro in pts with unresectable locally advanced or metastatic BRAF V600-mutant cutaneous melanoma. Here we present the SLI results. Methods: Key inclusion criteria were histologically confirmed unresectable/metastatic BRAF V600E/K-mutant cutaneous melanoma and ≤1 prior systemic therapy for unresectable/metastatic disease. Pts received enco 450 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO450+P) or enco 300 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO300+P). The primary objective was to identify the recommended phase 3 dose (RP3D). The primary endpoint was dose-limiting toxicity (DLT) incidence; secondary endpoints included safety, objective response rate (ORR), time to response (TTR), and PFS (post hoc). Results: 20 pts received COMBO450+P and 17 COMBO300+P (cutoff: Dec 2, 2022). See table for baseline characteristics. 1 pt had a DLT with COMBO450+P: Grade (G) 3 drug-induced liver injury with concurrent G4 ALT increase and G3 bilirubin increase that resolved. 2 pts had DLTs with COMBO300+P: 1 with G3 rheumatoid arthritis flare and 1 with inability to receive drug due to G4 arthralgia, G4 back pain, G4 pyrexia, G3 chills, G3 headache, G3 paranesthesia, and G3 maculopapular rash. Drug-related AEs led to permanent discontinuation in 4, 5, and 6 pts for enco, bini, and pembro, respectively. 1 pt in the COMBO300+P arm died <28 days after discontinuing all study treatments due to disease progression. See table for antitumor activity data. Conclusions: Safety across cohorts was comparable and consistent with the known safety profile of each agent. Both regimens were generally tolerable; COMBO450+P was chosen as the RP3D based on the totality of the safety data. The phase 3 portion of STARBOARD is ongoing. Clinical trial information: NCT04657991 . [Table: see text]
Determinants of racial disparities in immune-related adverse events (irAE) with checkpoint inhibition (ICI) in melanoma.
Authors: Ibrahim Milad , Angulo Paola , Fa'ak Faisal , Abdel-Wahab Noha , Diab Adi , Mehnert Janice M. , Weber Jeffrey S. , Lund Amanda , Schober Markus , Zhong Judy , Osman Iman
Published: June 2023

9549

Background: We recently reported that a pretreatment autoantibody (AutoAb) signature predicts immune-related adverse events (irAE) with an AUC of ~0.80 in melanoma patients enrolled in two phase III clinical trials of adjuvant ICI (Johannet et al. CCR 2022). The vast majority of those patients were non-Hispanic whites (NHW). We hypothesized that underrepresented minority (URM) melanoma patients might have a different baseline autoAb profile compared to NHW patients, as their site-specific irAEs differ ( Xue Bai et al. Br J of Derm 2022) and autoimmune disease is generally more common in underrepresented minorities (Roberts MH, Erdei E. Autoimmune Review 2020). We also explored the possibility that differences in the immuno-biology of acral melanoma (AM) and cutaneous melanoma (CM) – most commonly detected in URM and NHW patients, respectively – might inform our understanding of the racial differences in irAEs. Methods: We compared pre-treatment sera autoAb from URM melanoma patients (n=35) to NHW patients (n= 185) enrolled in Checkmate-238 (NCT02388906), Checkmate-915 (NCT03068455) or the NYU melanoma program database using the CDI and Sengenics proteomic platforms, and analyzed their association(s) with the development of grade 3-4 irAEs. We carried out single cell RNA-seq in AM versus CM tumor tissues to test whether expression of genes whose proteins were associated with irAE were preferentially expressed in AM tissue. We also compared RNA-seq of an immunoregulatory gene panel in AM versus CM tumors. Results: We identified autoAbs that were only detected in sera from URM patients with grade 3-4 irAEs (e.g. ALDOA, BANK1, LDHB and RNF7) and autoAbs that were only detected in NHW patients with grade 3-4 irAEs (e.g. GMEB2, YWHAE and ANKRD45). A subset of these autoAb targets was preferentially expressed in AM or CM tissues, while other targets were undetected in these melanoma subtypes. Cytokine signaling pathways were enriched in sera from URM but not NHW patients, and expression of genes known to modulate irAEs and response to ICI were significantly more expressed in AM than CM tumors, e.g. FOXP3 ( P=0.01), IL2 ( P=0.00547), IL4 ( P=0.0221) and IL10 ( P=0.0126). Conclusions: Our data suggest that URM patients have an altered tumor immune microenvironment that defines their response to ICI and risk of developing irAE. An integrative analysis of both the tumor and systemic immune environments is needed to better understand molecular links between response to ICI and irAEs in URM and NHW melanoma patients. A multi-center study is planned to address these questions.
Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An indirect treatment comparison (ITC) using patient-level data (PLD).
Authors: Schadendorf Dirk , Tawbi Hussein A. , Lipson Evan J. , Hodi F. Stephen , Ascierto Paolo Antonio , Larkin James , Lao Christopher D. , Grob Jean-Jacques , Ejzykowicz Flavia , Moshyk Andriy , Horton Viviana Garcia , Zhou Jenny , Xin Yiqiao , Palaia Jennell , McDonald Laura , Keidel Sarah , Salvatore Anthony , Sakkal Leon A. , Long Georgina V.
Published: June 2023

9552

Background: NIVO + RELA and NIVO + IPI are approved as dual checkpoint inhibitor, 1L treatment options for patients (pts) with advanced melanoma based on results from the RELATIVITY-047 (NIVO + RELA vs NIVO; enrollment, 2018–2020) and CheckMate 067 (NIVO + IPI or NIVO vs IPI; enrollment, 2013–2014) trials, respectively. However, there is no head-to-head trial comparing the combinations; therefore, this ITC was conducted using PLD. Methods: To adjust for cross-trial imbalances in baseline characteristics, inverse probability of treatment weighting (IPTW) was used. Database locks were selected to best align follow-ups in RELATIVITY-047 (min., 21 mo; median, 25 mo) and CheckMate 067 (min., 28 mo; median, 29 mo). Efficacy and safety outcomes were selected based on data availability, including progression-free survival (PFS) per investigator, confirmed objective response rates (ORRs) per investigator, overall survival (OS), treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation (DC). Efficacy was also evaluated in key subgroups. PFS and OS were compared for NIVO + RELA vs NIVO + IPI using Kaplan–Meier curves and hazard ratios (HRs); ORRs were compared using odds ratio (OR). As an internal validation of the ITC and matched assessments, the weighted NIVO cohorts from both trials were compared. Results: After IPTW, key baseline characteristics were balanced for NIVO + RELA (n = 340) and NIVO + IPI (n = 298). PFS, confirmed ORR, and OS after IPTW were similar between the treatments (table). Efficacy outcomes appeared to be similar between the treatments across subgroups, although trends favoring NIVO + IPI were observed for certain subgroups, such as pts with BRAF mutant disease or lactate dehydrogenase more than twice the upper limit of normal. Grade 3/4 TRAEs occurred in 23% and 61% of pts receiving NIVO + RELA and NIVO + IPI, respectively; any-grade TRAEs leading to DC occurred in 17% and 40% of pts. Efficacy outcomes were similar between the NIVO cohorts (table). Conclusions: In the absence of head-to-head trials, this ITC suggests that 1L treatment with NIVO + RELA may have comparable efficacy to, and better tolerability than, NIVO + IPI in pts with advanced melanoma. Similar outcomes between the NIVO cohorts support the ITC methodology. Results should be interpreted with caution given differences in study design and changes in treatment landscape over time. [Table: see text]
Melanomas lacking HLA class I expression and response to checkpoint inhibitor.
Authors: Chapman Paul B. , Jayaprakasam Vetri Sudar , Callahan Margaret K. , Shoushtari Alexander Noor , Postow Michael A. , Lezcano Cecilia , Wolchok Jedd D. , Nandakumar Subhiksha , Chatila Walid Khaled
Published: June 2023

9553

Background: The current paradigm of how checkpoint inhibitors (CPIs) mediate anti-tumor effects relies on αβ T cells as the effector cells. However, HLA class I allele expression loss is common in melanoma, and in some cases, both β2-microglobulin (β2m) alleles are silenced, which results in complete loss of HLA I expression. We reasoned that if CPI therapy requires αβ T cells as the effector cells, melanoma tumors with biallelic loss of β2m could not present antigen to αβ T cells and should never respond to CPI. Methods: We screened the 2754 melanoma patients (pts) whose tumors had been genotypically analyzed using MSK-IMPACT, a hybridization capture-based next-generation assay for targeted deep sequencing of all exons and selected introns of up to 505 genes, including β2m. We identified 13 pts who had been treated with CPI, were evaluable for response and progression-free survival, and whose pre-treatment melanoma was found to have biallelic loss of β2m. In 1 pt, only a post-treatment tumor was available for genetic testing for β2m loss but lack of β2m expression in a pre-treatment tumor was confirmed by immunohistochemistry (IHC). Pts were assessed for clinical responses using RECIST 1.1. We recorded best overall response, duration of response, and overall survival. When available, pre-treatment tumor tissue was assessed by IHC for β2m and HLA class I expression, and for lymphocytic infiltrates expressing CD3, CD4, CD8, and CD56. Results: Anti-tumor responses were observed in 3/13 patients (23%); 2 PRs, 1 metabolic CR lasting for 24, 9.4, and 6.4 months, respectively. Responses were to ipilimumab (ipi) (N=2) and ipi/nivolumab (N=1). One pt responding to ipi had progressed on pembrolizumab; the other 2 responders were treatment-naïve. One pt died 11.5 months after starting treatment; the other 2 pts remain alive 5.5 and 8.9 years after starting treatment. IHC confirmed the lack of cell surface expression of β2m and HLA class I in all 5 tumors available for IHC staining. IHC evaluations of lymphocyte infiltrates in tumors from 1 responder and 4 non-responders showed variable degrees of CD3+ tumor infiltrating lymphocytes (TIL) with CD4+ T cell predominance. Interestingly, the 1 responder had the least dense pretreatment TIL among the 5 cases. In all 5 tumors, CD56+ lymphocytes, indicating NK cells, were rare-to-absent. Conclusions: Melanomas lacking HLA class I expression can respond to CPI therapy. Although all patients ultimately progressed, some responses were long-lived and 2 of 3 patients remain alive >5yrs. It seems unlikely that traditional CD8+ T cells are mediating these responses but more work needs to be done to identify the effector cells in these cases.
Population-based validation of the melanoma institute australia (MIA) and the memorial sloan-kettering cancer center (MSKCC) predictive tool for sentinel node status in patients with melanoma.
Authors: Mikiver Rasmus , Olofsson Bagge Roger , Marchetti Michael A. , Van Akkooi Alexander Christopher Jonathan , Coit Daniel G. , Ingvar Christian , Isaksson Karolin , Scolyer Richard A. , Thompson John , Varey Alexander , Lyth Johan , Bartlett Edmund
Published: June 2023

9571

Background: Patients with primary cutaneous melanoma are selected for sentinel lymph node biopsy (SLNB) based upon their risk of a positive SLN being identified. To improve upon stage-based categorization, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models. Which model is more clinically useful is currently unclear. Methods: Consecutive patients undergoing SLNB from 2007-2021 were identified from the Swedish Melanoma Registry (SweMR), which covers 99% of patients with invasive cutaneous melanoma in Sweden. The predicted probability of SLN positivity was calculated using the MSKCC and limited MIA models (using mitotic rate as absent/present instead of count and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The “clinical utility” of each model was assessed using decision curve analysis (DCA) and compared with a strategy of performing SLNB on all patients. Results: In total 10,089 patients were included; the median Breslow thickness was 1.8 mm, 33.7% were ulcerated, and 1,802 patients had a positive SLN (17.9%). Both the MSKCC and limited MIA models were well calibrated across the full range of predicted probabilities, and had similar external area under curve (AUC), MSKCC 70.8% (95% CI 69.5-72.1%) and MIA 70.3% (95% CI 68.9-71.7%). When new models were constructed to compare the incremental value of the additional parameters of either nomogram over Breslow thickness alone, the AUCs were 70.1%, 71.6% and 72.0% for Breslow alone, MIA parameters and MSKCC parameters, respectively. At a risk threshold of 5%, DCA indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all. The greatest benefit was observed from use of the models in patients with T2 melanomas when a threshold of 10% was used to select patients for SLNB. In that setting, use of the nomograms led to a net reduction in seven avoidable SLNBs per 100 patients for the limited MIA nomogram and eight for the MSKCC nomogram, when compared to a strategy of SLNB for all. Conclusions: This study confirms the statistical performance of both the MSKCC and limited MIA models in a large, nationally-representative dataset. However, clinical utility as assessed by DCA demonstrated that using the models only improved selection for SLNB when a risk threshold of at least 10% was employed, and then mainly for T2 melanomas. Either further development of the nomograms, or other strategies, are needed to improve selection at lower risk thresholds.
Tumor-informed circulating tumor DNA (TI-ctDNA) based molecular residual disease (MRD) detection and relapse risk for patients with stage II-IV melanoma in surgical remission: A single center experience.
Authors: Rhea Logan , Daniels Megan , Sabo Roy , Poklepovic Andrew Stewart
Published: June 2023

9572

Background: Melanoma is associated with significant risk of relapse after surgery. While the odds of relapse increase with advancing stage, long term relapse free survival (RFS) is possible without adjuvant therapy in a significant subset of patients as shown by AJCC v8 staging long term survival data. TI-ctDNA (Signatera™) is a non-invasive biomarker for MRD detection and functions by sequencing the patient’s own tumor for the creation of a customized panel of PCR probes based upon a tumor’s unique mutational profile. Positive TI-ctDNA testing is significantly associated with relapse after surgical resection in colorectal cancer and may help inform treatment decision-making, allowing for intensification or de-intensification of patient management. This study describes the operating characteristics of TI-ctDNA in monitoring for relapse in patients with resected melanoma. Methods: This is a single center retrospective analysis of patients with stage IIb-IV melanoma in surgical remission. Between January 2021 and January 2023, male and female patients presenting in surgical remission were monitored with TI-ctDNA at 6- or 12-week intervals. Surveillance imaging for relapse was performed according to standard of care guidelines appropriate for tumor stage. Patients were treated with immunotherapy, targeted therapy, or melanoma specific anti-tumor vaccine. Duration of RFS from surgery to detectable TI-ctDNA was recorded, along with duration of RFS from surgery to confirmed melanoma relapse. Results: 45 eligible patients were included in the analysis. 10 patients had detectable TI-ctDNA during the study period. 7 patients had confirmed relapse, 6 of whom were TI-ctDNA positive and 1 who was TI-ctDNA negative. The total relapse rate in TI-ctDNA positive patients (6/10) was significantly higher than the relapse rate in TI-ctDNA negative patients (1/35) [p = 0.0002]. Time to detection of positive TI-ctDNA was variable and ranged from 0 to 664 days (median 73 days). Conclusions: TI-ctDNA testing demonstrated preliminary ability to differentiate melanoma patients at the highest risk of relapse. Prospective evaluation of TI-ctDNA monitoring for determination of patients at high versus low risk of relapse is warranted and may help to inform future clinical trial designs by allowing for patient stratification to low risk (undetectable TI-ctDNA) and high risk (detectable TI-ctDNA) disease states.
Discovery and validation of AMBLor as a prognostic biomarker for non-ulcerated cutaneous AJCC stage I/II melanoma.
Authors: Lovat Penny , Ewen Tom , Podlipnik Sebastian , Puig Susana , Malvehy Josep , Clark Priscilla , Lewis Claire , Paragh Gyorgy , Bogner Paul , Mailer Sonia , McArthur Grant A. , Husain Akhtar , Stefanos Niki , Barrett Paul , Labus Marie , Sloan Philip
Published: June 2023

9573

Background: Cutaneous melanoma incidence continue to increase, with a particular increase in the number of patients diagnosed with thin, < 1mm tumours with reduced probability of recurrence-free survival. The inability of current AJCC staging criteria to identify genuinely low risk subsets of patients with AJCC stage I/II tumours thus emphasises the acute need for credible prognostic biomarkers to stratify patient follow-up based on personalised risk. The combined immunohistochemical (IHC) expression of AMBRA1 and Loricrin (AMBLor) in the epidermis overlying non-ulcerated AJCC stage I melanomas has recently been identified as a prognostic biomarker and valuable pre SLNB test. The aim of the present study was to evaluate the potential for AMBLor as a prognostic biomarker for both AJCC stage I and II non-ulcerated melanoma. Methods: Prospective analysis of AMBLor was performed in two independent retrospective cohorts of non-ulcerated AJCC (8th edition) stage I and II cutaneous melanomas derived from the USA and Australia (discovery cohort) and Spain and the UK (Validation cohort) following validated automated immune-histological staining and binary scoring analysis to define at risk vs low risk subgroups. Each cohort was powered to represent rates of 10% or up to 20% metastasis for stage I or stage II disease respectively. Results: Data revealed retention of AMBLor in the discovery cohort of 541 melanomas correlated with significantly increased recurrence-free survival (RFS) of 96% compared to 87% for patients with stage I/II melanomas in which AMBLor was lost (P = 0.06; HR 3.6, 95% CI 1.99-6.84, NPV 96%). Subsequent AMBLor analysis in the validation cohort of 303 tumours, further confirmed retention of AMBLor was associated with increased RFS of 98% compared to 81% for patients with stage I/II tumours in which AMBLor was lost (P = 0.01; HR 8.16, 95% CI 3.68-18.07). Conclusions: Collectively data from this multi-international study confirm AMBLor as a prognostic biomarker marker able to identify genuinely low risk subsets of AJCC stage I/II melanomas. Inclusion of AMBLor into clinical melanoma management may therefore aid stratification of patient follow up, enable significant savings on healthcare resources and improve patient anxiety.
Melanoma disparities in urban vs rural communities in the era of immunotherapy: An NCDB analysis.
Authors: Akers Rachel , Coogan Alison , Kasper Laura , Krishnan Vaishnavi , Tan Alan , O'Donoghue Cristina
Published: June 2023

9578

Background: Several barriers to care exist for melanoma patients including distance to specialty care, transportation, and cost. Additionally, differences in rural and urban melanoma incidence have not been fully investigated. Using a large nationwide database, we aim to investigate the relationship between urban and rural locations in stage of melanoma presentation and access to adjuvant systemic treatment. Methods: The National Cancer Database (NCDB) was queried for all adult patients (≥ 18 years old) with diagnosis of cutaneous melanoma from 1/1/2011 – 12/31/2020. For receipt of adjuvant immunotherapy, diagnosis from only 1/1/2017 - 12/31/2020 was analyzed. Demographic, socioeconomic, tumor-related, and treatment-related factors were analyzed using SPSS Statistics, with Chi-square analysis performed for categorical variables and ANOVA performed for continuous. Results: Between 2011 and 2020, 558,445 patient cases were identified and included in the analyses. The average age was 63.7 years, and patients predominantly identified as White (97.6%) and non-Hispanic (96.2%). Patients in urban areas were more likely to present with melanoma of the extremities (40.8% vs 36.2%, p < 0.001), while patients in rural areas presented with head and neck melanoma (26.2% vs 31.0%, p < 0.001). Additionally, patients in urban areas were more likely to have an early-stage melanoma (0, 1, or 2) melanoma (51.4% vs 48.5%, p < 0.001). Patients in rural areas traveled an average of 68 miles for care, in contrast to urban patients who traveled an average of 20 miles (p < 0.001). There was no significant difference when comparing receipt of immunotherapy for stage 3 or stage 4 patients. Conclusions: In rural areas, patients with melanoma tended to present with a higher portion of head and neck melanoma and of later stage. Rural patients also had to travel farther for care. However, these differences did not result in fewer patients in rural areas receiving immunotherapy for appropriate treatment. Further studies are needed to evaluate how these presentation differences influence care outcomes.
A pilot study of the neoadjuvant use of vemurafenib plus cobimetinib in patients with BRAF-mutant melanoma with palpable lymph node metastases: Survival results.
Authors: Petrella Teresa M. , Mihalcioiu Catalin Liviu Dragos , Nessim Carolyn , Spatz Alan , Watson Ian , Wright Frances Catriona
Published: June 2023

9579

Background: Melanoma patients with palpable nodal metastases have a very poor prognosis with the majority recurring within the first 2-3 years post-resection with survival ranging from 20-50% at 5 years. We aimed to ascertain if patients with a BRAF V600 mutation that receive vemurafenib and cobimetinib before surgery (neoadjuvantly) have a higher probability of resectability, pathologic complete response (pCR), and a lower risk of local recurrence and a longer disease free survival (DFS), distant metastatic free survival (DMFS) and overall survival (OS). Methods: This was a single arm, prospective, multi centre phase II study in patients with histologically confirmed, BRAF V600 mutated Stage IIIB and IIIC melanoma (AJCC 7th Edition) with palpable nodal disease. Patients received vemurafenib 960mg PO BID and cobimetinib 60mg PO OD for 4 months prior to resection followed by 8 months of adjuvant therapy post-surgery. CTscans were performed at baseline and before resection and every 6 months for the first 3 years and yearly in year 4 and 5. Biopsies for correlative studies and diagnosis were performed at baseline prior to starting therapy. The primary outcomes were the proportion of patients achieving resectability, radiologic response as per RECIST and the proportion of patients achieving a pCR. Presented here are the LRFS, DMFS, DFS and OS. Results: Twenty-four patients were enrolled and received neoadjuvant vemurafenib and cobimetinib and 21 underwent resection. Following resection and pathological evaluation 12 (57%; 95% CI 34.02-78.18)) patients achieved a pCR, 8 (38%; 95% CI 18.11-61.56) had a partial pathologic response and 1 had no pathologic response. Of the 24 patients, 2 patients (8%) developed local recurrence, 6 patients (25%) developed distant metastasis, and 8 patients (33%) had either local or distant recurrences. 7 patients (29%) died due to metastatic disease. At 60 months, LRFS was 89.5% (76.7-100%), DMFS was 75.0% (59.5-94.5%), DFS was 85.7% (72.0-100%), and OS was 63.9% (95% CI 43.5-93.8). Among total 20 evaluable patients, 17 patients had CR/PR and 3 had PD/SD as best response. There was no significant difference between patients with CR/PR or SD/PD (log-rank p-value = 0.0548) with 48 month survival of 82.4% for CR/PR population compared to 33.3% with SD or PD. Conclusions: In this small phase II study, neoadjuvant vemurafenib and cobimetinib led to a higher LRFS, DMFS, DFS and OS of all resected patients with bulky nodal disease compared to historical survival rates. Clinical trial information: NCT02036086 .