bluuebunny/crossref_metadata_2025 huggingface dataset:
Contemporary biomarker testing rates in both early and advanced NSCLC: Results from the MYLUNG pragmatic study.
Authors: Evangelist Makenzi Colleen , Butrynski James Edward , Paschold John C. , Ward Patrick J. , Spira Alexander I. , Ali Kashif , Espirito Janet L. , Hakimian David , Jotte Robert M. , Koselke Beth , Larson Timothy , Meshad Michael W. , Neubauer Marcus A. , Ogden Katie , Owera Rami , Richards Donald A. , Robert Nicholas J. , Walberg Jennifer M. , Wang Yunfei , Coleman Robert L.
Published: June 2023

9109

Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study aims to identify and overcome barriers to timely and appropriate biomarker testing in patients (pts) with NSCLC. We previously reported retrospective real-world testing rates for 5 biomarkers from 2018-2020 in metastatic pts. We now report results from the prospective observational phase, including additional biomarkers in pts with both early and advanced NSCLC. Methods: This was a prospective, non-interventional cohort study of newly diagnosed pts with early stage (ES), locally advanced (LA), or metastatic NSCLC (mNSCLC) between 12/2020 and 9/2022 and enrolled from 12 community practices (69 sites) across The US Oncology Network. The proportion of pts with test results for 9 biomarkers at time of protocol initiation were examined: ALK, BRAF, EGFR, ROS1, PD-L1, KRAS, MET, NTRK, and RET. Timing of tests, use of single vs multigene NGS testing, clinical and socioeconomic factors, and reasons for not testing were collected in real time. Results: Of 1002 pts screened, 987 were enrolled and analyzed. There were 405 stage IB-IIIC pts [n = 284 stage IB-IIIA (ES cohort); n = 121 stage IIIB-IIIC (LA cohort)] and 582 stage IV pts (mNSCLC cohort). Descriptions for ES and LA vs mNSCLC pts respectively include median age 68 vs 69 yrs, 49% vs 52% female, 83% vs 77% white, 58% vs 79% adenocarcinoma histology, 71% vs 68% ECOG 0-1, and 33% vs 30% high school education level. Testing rates for ES vs mNSCLC cohorts are shown in the table below: prior to treatment initiation, 64% of ES and 83% of mNSCLC pts had at least one biomarker result; and 37% of mNSCLC pts had results for all 9 biomarkers. NGS testing occurred in 37% and 57% of the ES and mNSCLC cohorts respectively. Reasons for not testing included: barriers to ordering (42%, 25%), insufficient tissue (18%, 18%), clinical deterioration/crisis (5%, 12%), and other reasons (37%, 49%), respectively. Conclusions: As more genomic alterations are identified in NSCLC, we observed that many pts do not get full genotyping prior to treatment, and biomarker testing remains of utmost importance. Further analyses by distinct stages (e.g. LA), histology, social determinants, utilization of targeted therapies, and other reasons for not testing will be performed. These data will be used to evaluate future prospective interventions for MYLUNG, to help improve comprehensive biomarker testing for NSCLC. [Table: see text]
Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.
Authors: Shi Yuankai , Hu Xingsheng , Li Xingya , Li Yongsheng , Wang Ke , Wang Pingli , Jiang Liyan , Zhang Shucai , Meng Xiangjiao , Wang Huijuan , Dong Xiaorong , Yang Runxiang , Luo Yongzhong , Mei Qi , Sun Yinghui
Published: June 2023

9110

Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .
First-in-human, multicenter phase Ⅰ study of TGRX-326 in patients with advanced ALK-positive non-small cell lung cancer.
Authors: Zhao Hongyun , Ma Yuxiang , Yang Nong , Wang Zhehai , Jin Wenjian , Li Xingya , Liu Yunpeng , Meng Rui , Zhou Jianying , Cheng Ying , Wang Yongsheng , Yu Zhuang , Zhang Li
Published: June 2023

9113

Background: TGRX-326, a deuterated derivative of lorlatinib (LOR), is a potent 3rd generation ALK and ROS1 dual TKI with high potency against multiple ALK-resistant mutations. Deuteration of the key metabolic site of the molecule allows to achieve a higher exposure than with LOR and this may result in alleviated toxicities and better efficacy. Methods: The study comprised 3 phases: dose escalation (D-ESCAL), dose expansion (D-EXP) and cohort expansion (C-EXP). In D-ESCAL and D-EXP, ALK+ pts prior failed on 2nd gen ALK-TKIs or ROS1+ pts resistant to crizotinib (CRZ) were enrolled; in C-EXP, ALK+ pts progression after CRZ (C-EXP-A1),progression after ≥1 2nd gen TKIs (C-EXP A2), ROS1+ progression after CRZ (C-EXP-B) and pts with ALK TKI naïve (C-EXP-C) were enrolled. Results: Up to Jan 13, 2023, 185 pts (median age 53 years, 45.9% male) were enrolled; Median treatment and follow-up was 5.5 and 6.7 months, respectively. There were no DLT observed and no MTD identified in D-ESCAL (5-125mg QD, n=19). Based on the safety, efficacy and PK exposure data of 42 pts in D-ESCAL and D-EXP, 60 mg QD was selected as the RP2D for C-EXP,the average AUCtau of 60mg QD reached to 5443ng*hr/mL. Treatment-related adverse events (TRAEs) occurred in 87.5% patients (162/185), the most common TRAEs were hypercholesterolemia (74.1%), hypertriglyceridemia (68.1%), weight gain (36.2%), peripheral edema (15.7%), peripheral neuropathy (14.1%). As for R2PD, 132 of 155 (85.2%) experienced TRAEs, Grade ≥3 TRAEs occurred in 19.7%, most frequent were hypertriglyceridemia (11%) and hypercholesterolemia (8.4% ). Dose interruptions and dose reductions associated with TRAEs were reported in 10 (5.4%) and 5 (2.7%) pts respectively. Confirmed response were observed in 142 ALK+pts enrolled in C-EXP, results are shown in the Table (Efficacy of B-ROS1+ pts will be reported separately). Eleven ALK mutations were detected in 16 pts (either alone or in combination); 50.0% pts achieved PR. Out of 6 pts who were positive for G1202R, 50.0% experienced PR. Conclusions: TGRX-326 was well tolerated in pts with advanced ALK+ NSCLC and showed promising clinical antitumor activity irrespectively of ALK+ resistance to CRZ and 2nd gen TKIs, especially among those with brain metastases. Impressive activity was seen in ALK TKI naïve NSCLC. TGRX-326 demonstrated antitumor activity against multiple ALK mutations including G1202R. Clinical trial information: NCT05441956 . [Table: see text]
Characteristics of long-term survivors with EGFR mutant (EGFRm) metastatic non-small cell lung cancer (mNSCLC).
Authors: Marmarelis Melina Elpi , Grady Connor B. , McCoach Caroline , Sun Fangdi , Liu Geoffrey , Patel Devalben , Nieva Jorge J. , Marrone Kristen A. , Velcheti Vamsidhar , Liu Stephen V. , Patil Tejas , Weiss Jared , Schwartzman William , Villaruz Liza C , Cass Amanda , Aisner Dara L. , Hwang Wei-Ting , Aggarwal Charu , Camidge D. Ross , Sun Lova
Published: June 2023

9116

Background: Although osimertinib has become standard first-line (1L) therapy for patients (pts) with EGFRm mNSCLC, a subset treated with earlier-generation EGFR-targeted TKIs and chemotherapy have had long-term survival. We sought to characterize clinical features of long-term survival in pts with EGFRm mNSCLC treated prior to the osimertinib era. Methods: Data were abstracted from electronic medical records at 12 cancer centers participating in the Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC). We included patients with mNSCLC with sensitizing mutations in EGFR who started 1L systemic therapy before 2015. Survival distributions and predictors were assessed using Kaplan-Meier estimates and a multivariable Cox proportional hazards model including time-dependent brain metastasis (met) development, age, 1L therapy (targeted vs. chemotherapy), sex, race, and smoking status. Multivariable logistic regression was used to evaluate baseline predictors associated with 5+ year survival vs. not for those with known survival status at 5 years after start of 1L. Results: We identified 304 patients (69% female, 56% White, 29% Asian, mean age 61.2). First-line targeted therapy was given in 70% of patients. With a median follow-up of 81.5 months, median overall survival was 63.5 months (95% CI 59.4-71.9). 135 (44%) pts survived 5+ years; among those with baseline next-generation sequencing (NGS), presence of a baseline pathogenic ERBB2 variant was higher in 5+ year survivors (4/51 [8%], 2x amplification, y772_A775dup, S310F) v others (1/65 [2%], amplification). Among 161 pts with baseline brain imaging, both baseline and on-treatment development of brain mets were associated with worse survival (HR 1.29, 95% CI 1.21-1.37; HR 1.59, 95% CI 1.47-1.72; both P < 0.001). Excluding 22 patients lost to follow-up before 5 years, a history of smoking (OR 2.99, 95% CI 1.35-6.90, P = 0.008) and baseline brain metastases (OR 3.57, 95% CI 1.64-8.13, P = 0.002) were associated with death before 5 years. Conclusions: Long-term survivors with EGFRm mNSCLC treated before the osimertinib era were more likely to be nonsmokers and have no baseline brain metastases. This highlights a subset of EGFRm patients who had excellent outcomes with older treatment strategies and may not benefit as much from intensification approaches. Additional baseline mutational data will be presented at the conference.
Stimulator of interferon gene (STING) expression as a biomarker for overall survival in PDL1-negative, TMB-low non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).
Authors: Hadfield Matthew James , Gandhi Nishant , Farrell Alex Patrick , Azzoli Christopher G. , Vanderwalde Ari M. , Halmos Balazs , Liu Stephen V. , El-Deiry Wafik S. , Naqash Abdul Rafeh
Published: June 2023

9120

Background: cGAS-STING (CGS) is an intracellular DNA sensing pathway that when activated, stimulates interferon and other immune-related signaling pathways. While increased expression of CGS-related genes has been associated with better survival in NSCLC, studies investigating this phenomenon in tumors less likely to respond to ICIs such as PDL1-negative, TMB-Low NSCLC are lacking. Here we report the role of CGS pathway in NSCLC tumors that are both PDL1-negative and TMB-Low. Methods: DNA (592-gene or whole exome) and RNA sequencing (whole transcriptome) was performed for NSCLC specimens (n=7264) submitted to Caris Life Sciences (Phoenix, AZ). PDL1 negativity was defined as <1% TPS score (22C3) & TMB-Low as <10 mutations/Mb. Hierarchical Agglomerative Clustering (HAC) was performed on STING pathway genes (CXCL10, CCL5 and GZB) and tumors were grouped into STING-high (n=3070), STING-intermediate (n=1609) and STING-low (n=2585) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate cellular composition of immune cells. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q<0.05). Kaplan Meier method was used to estimate the overall survival (OS) derived from insurance claims of IO treated pts with NSCLC (n=400). Pts were stratified into groups above or below the median expression of the STING gene ( TMEM173). Results: Compared to STING-low, tumors that were STING-high had enrichment in immune cell infiltrates including CD8+ T cells (4.4-fold) and B-cells (5.9-fold); Additionally, STING-high cohort had significantly higher expression of immune checkpoint (IC) genes including CD274(2.5-fold), CD80 (2.7-fold, all q<0.05). STING-high tumors also had a higher prevalence of TP53 mutations (mts) and a lower prevalence of STK11 and KEAP1 mts (Table). Median overall survival (OS) was 21.1 months in the STING-high cohort (n=200) vs 11.9 months in the STING-low cohort (n=199) in IO treated pts (HR = 0.62, p<0.000.1) Conclusions: To our knowledge this is the largest real-world dataset indicating that enrichment of both the STING gene, and gene signatures associated with the STING pathway represent valuable transcriptomic biomarkers to stratify pts with PDL1-negative and TMB-Low NSCLC who benefit more from IO therapies. Conversely, novel IO combination strategies need to be employed in STING-low tumors to enhance outcomes. [Table: see text]
Amplification of wild-type RET and clinical response to selpercatinib for non–small-cell lung cancer (NSCLC).
Authors: Gandhi Malini Marion , Ricciuti Biagio , Gildenberg Melissa , Singh Ankit , Li Yvonne Y. , Gagné Andréanne , Wang Xinan , Fitzgerald Kelly , Aizer Ayal , Nishino Mizuki , Alessi Joao Victor Machado , Pecci Federica , Di Federico Alessandro , Fisch Adam , Nardi Valentina , Sholl Lynette M. , Awad Mark M. , Rotow Julia K.
Published: June 2023

9123

Background: RET rearrangements and RET kinase domain mutations represent targetable genomic alterations in various cancer types. However, the frequency and characteristics of RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. Methods: In a pan-cancer cohort of patients at the Dana-Farber Cancer Institute (DFCI) whose tumors underwent next-generation sequencing (NGS), we evaluated the frequency of wild-type (wt) RET amplification (defined as ≥6 copies) in the absence of RET rearrangements or activating mutations. We validated our findings using merged data from the TCGA, GENIE, and China Pan-Cancer datasets. Results: The frequency of wt RET amplification across all cancers was 0.08% (28/34,463) in the DFCI cohort and 0.16% (145/91,466) in the validation cohort. In NSCLC, the frequency of RET amplification was 0.10% (5/4773) in the DFCI cohort and 0.13% (15/11,622) in the validation cohort. Other cancer types with RET amplification included hepatobiliary cancer, prostate cancer, and breast cancer, among others. For 22 RET-amplified cases with available copy number data , the median RET gene copy number was 7 (range 6-36). Among 20 RET-amplified NSCLCs, 10 had no other known driver mutations, and 10 had concurrent driver mutations (including MET exon 14 skipping, MET amplification, KRAS G12C/S/D, EGFR L858R, EGFR exon 20 insertion, and EGFR exon 19 deletion). In cases with available smoking status, 5 out of 6 patients with RET-amplified NSCLC had a history of tobacco use. A 69-year-old man with unresectable stage III NSCLC had disease recurrence after chemoradiation and durvalumab. Both the initial and recurrent biopsy samples showed focal high-level RET amplification (22 and 28 copies, respectively); genomic and RNA sequencing showed no other driver mutations or RET rearrangements. He experienced partial response to the selective RET inhibitor selpercatinib with decrease of both intracranial and systemic tumor burden. Conclusions: Amplification of wt RET represents a novel, targetable, rare molecular subset of NSCLC and other cancers.
Results from a first-in-human phase 1B study of a complement factor H inhibitor (GT103) in patients with non-small cell lung cancer (NSCLC).
Authors: Clarke Jeffrey Melson , Stinchcombe Tom , Gu Lin , Mamdani Hirva , Antonia Scott Joseph , Simon George R. , Sonpavde Guru P. , Ready Neal E. , Crawford Jeffrey , Campa Michael , Gottlin Elizabeth , Bushey Ryan , Herndon James Emmett , Patz Edward
Published: June 2023

9128

Background: GT103 is a first-in-class IgG3 monoclonal antibody that was derived from a single human B cell and inhibits complement factor H (CFH). CFH is implicated in cancer immune evasion and overexpression portends a poor prognosis in multiple malignancies. CFH regulates C3 convertase in the alternative pathway of the complement cascade, limiting downstream opsonization and membrane attack complex formation. Monoclonal antibody inhibition of CFH facilitates complement-dependent tumor cell lysis, modulates the adaptive immune response, and inhibits tumor growth. Methods: GT103 is being evaluated in a multi-institutional, first-in-human, phase Ib study in patients with advanced stage, refractory NSCLC. A standard ‘3+3’ dose escalation schema was used across four dose levels, with treatment given until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) observation period included cycle 1 and radiographic disease assessment was performed every 6 weeks. We have previously reported that no DLT was seen at the highest two dose levels of 3 mg /kg or 10 mg/kg administered IV every 3 weeks. Two expansion cohorts have now been opened at 10 mg/kg IV every 2 week and 15 mg/kg every 3 weeks dose levels allowing up to 6 patients at each dose level. We herein present updated clinical outcomes and analysis of correlative biomarkers. Results: As of February 3, 2023, twenty-five patients have been treated, with a median follow up of 230 days. Five of the 21 patients in the dose escalation cohort demonstrated stable disease by RECIST criteria. In the 10 mg/kg dose level, one patient has experienced prolonged disease stabilization and has received 12 cycles to date with tumor reduction on CT. The DLT period is ongoing for two patients enrolled in the 10 mg/kg IV every 2 weeks and two patients in the 15 mg/kg every 3 weeks expansion cohorts. Soluble C5b-9 (s C5b-9) is a candidate pharmacodynamic biomarker for GT103 and was measured at baseline and at day 15 from patients in all four dose escalation levels (0.3, 1, 3, 10 mg/kg). An increase in sC5b-9 was found in 13 of 21 patients at day 15. A marked doubling of the baseline sC5b-9 level was demonstrated in a subset of patients by day 15 indicative of biologic activity. Conclusions: GT103 is well tolerated in heavily pretreated advanced NSCLC population. Early clinical activity has been demonstrated to date with stable disease seen in 24% of patients. Updated clinical results and correlative data will be presented. A separate phase 2 study of combination GT103 with pembrolizumab is planned for patients with refractory NSCLC. Trial Registration: The study was approved by Duke University IRB with approval number Pro00104564. Clinical trial information: NCT04314089 .
Evaluating generalizability of practice-changing randomized clinical trials in non-small cell lung cancer using machine learning-based in-silico trials.
Authors: Orcutt Xavier , Mamtani Ronac , Sondhi Arjun , Cohen Aaron B. , Parikh Ravi Bharat
Published: June 2023

9130

Background: Results of randomized clinical trials (RCTs) of anticancer agents are not generalizable to many real-world patients. Advances in machine learning (ML) and increasing availability of curated real-world data offer opportunities to assess generalizability by simulating trials “in-silico”. Our objective was to assess the generalizability of survival outcomes reported in 2 practice-changing phase III trials in first-line (1L) advanced non-small cell lung cancer (aNSCLC). Methods: Our cohort included patients from the nationwide Flatiron Health EHR-derived de-identified database diagnosed with stage IIIB-IV or recurrent aNSCLC between 2011 and 2020. First, we trained and validated supervised ML models (gradient boosted, random forest, support vector machine and penalized Cox) to predict 1-year survival for patients with aNSCLC; the Lung Cancer Prognostic Index (LCPI), a published disease-specific prognostic index, was used as a comparator model. We used 130 demographic, vital sign, laboratory, and biomarker features at aNSCLC diagnosis to build models. Second, we used the best-performing ML model to create 4 prognostic risk groups. Third, we simulated 2 seminal trials for 1L treatment of aNSCLC, using inverse probability of treatment-weighted survival analyses, coarsely reproducing inclusion/exclusion criteria across ML-derived risk groups. We compared median overall survival (mOS) using Kaplan-Meier curves from the start of 1L treatment to death in in-silico trials (ISTs) vs. RCTs. Results: Our cohort included 61,339 patients with aNSCLC. The best-performing gradient boosted model outperformed the LCPI (AUC 0.784 vs 0.688). In ISTs, survival benefits of novel treatments varied across risk groups and were generally lower in ISTs compared to RCTs (Table). IST results in high- and very high-risk patients were inconsistent with RCT survival results. For example, for KEYNOTE-024, mOS in the pembrolizumab arm was 30.0 months, whereas in the IST, mOS among patients receiving pembrolizumab varied from 1.3 months in very high-risk patients to 41.5 months in low-risk patients. RCT results overestimated treatment effects for high-risk aNSCLC patients. Conclusions: ML-based ISTs can reveal heterogeneity in real-world survival outcomes associated with novel oncology treatments and elucidate populations for whom RCT results generalize poorly. [Table: see text]
Real-world outcomes of first-line immune checkpoint inhibitors with or without chemotherapy in KRAS G12C altered NSCLC according to PD-L1 status.
Authors: Aggarwal Charu , Parkar Lamisa , Huerga Iker , Sasser Kate , Nimeiri Halla , Korytowsky Beata , Patel Jyoti D.
Published: June 2023

9136

Background: There is a considerable debate whether treatment approaches should be tailored in advanced KRAS G12C-mutated NSCLC. Increasing evidence suggests that KRAS G12C-mutated NSCLC is associated with genomic heterogeneity that may impact clinical outcomes. Herein, we report a multimodal, real world outcomes analysis of 1L patients with advanced KRAS G12C-mutated NSCLC stratified by treatment type and PD-L1 status. Methods: Deidentified multimodal real-world data (RWD) of 1576 advanced, 1L NSCLC patients across the US were retrospectively analyzed from the Tempus database. Selection criteria included: Tempus xT targeted NGS, known PD-L1 status, absence of EGFR, ALK and ROS1 mutations, and treatment with chemotherapy (CT) + pembrolizumab (P), or P only. Patients were stratified by the presence or absence (wt) of KRAS G12C alterations. Median OS (mOS) was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS G12C status, PD-L1 status, and pathogenic alterations of STK11 and KEAP1. Results: In this study, two cohorts were assessed, KRAS G12C (n = 201) and KRAS G12C wt (n = 1375). Characteristics and demographics were balanced between both cohorts. Among TPS < 50 patients treated with CT + P, KRAS G12C (n = 109, 54%) had a mOS of 11.64 months (m) versus 16.81m (HR = 1.32, p = 0.06) for KRAS G12C wt (n = 864, 62.8%). Among TPS < 1 patients treated with CT + P, KRAS G12C (n = 46, 22%) had a mOS of 11.18 m versus 16.44 m (HR = 1.67, p = 0.01) for KRAS G12C wt (n = 489, 35%). Among TPS ≥50 patients treated with P only, KRAS G12C (n = 45, 22.3%) had a mOS of 30.03m compared to 25.03m (HR = 0.94, p = 0.83) in KRAS G12Cwt (n = 236,17.1%). TPS < 50 subgroup was enriched for select co-mutations with KRAS G12C ( STK11, 24.5%; KEAP1, 10.7%) vs. TPS ≥50 ( STK11, 3.8%; KEAP1, 5.1%). When evaluating the impact of co-mutations in the KRAS G12C with TPS < 50, STK11 (n = 30) mOS was 10.59m (HR = 1.01, p = 0.81) and KEAP1 (n = 13) mOS was 7.63m (HR = 2.14, p = 0.03). Conclusions: This largest RWD analysis to date demonstrates that 1L KRAS G12C NSCLC patients with TPS < 1% and < 50% receiving standard CT + P have the shortest survival among all evaluated sub-groups. Novel KRAS G12C targeted combination therapies in development for this patient population may offer the promise of better outcomes. [Table: see text]
Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC) (CheckMate 358).
Authors: Bhatia Shailender , Topalian Suzanne Louise , Sharfman William Howard , Meyer Tim , Lao Christopher D. , Fariñas-Madrid Lorena , Devriese Lot A. , Aljumaily Raid , Ferris Robert L. , Honma Yoshitaka , Khan Tariq Aziz , Srirangam Anjaiah , Garnett-Benson Charlie , Lee Michelle , Nghiem Paul
Published: June 2023

9506

Background: MCC is a rare and aggressive skin cancer. Programmed death-ligand 1 (PD-L1) is often upregulated in MCC and blockade of PD-L1 or its receptor, PD-1, has improved survival for patients with metastatic MCC. Anti–PD-1 combined with anti–CTLA-4 has been reported to improve outcomes over anti–PD-1 monotherapy (NCT03071406; Kim S et al., Lancet 2022), however further investigation is needed. CheckMate 358 (NCT02488759) assessed NIVO ± IPI in 2 non-randomized MCC cohorts. Methods: Eligible pts had recurrent or metastatic MCC, ≤ 2 prior therapies, ECOG performance status (PS) 0–1, and no prior immune checkpoint inhibitor (ICI) therapy. Pts were eligible regardless of PD-(L)1 status. Pts received NIVO 240 mg Q2W or NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W for ≤ 24 months (m) or until disease progression, unacceptable toxicity, or consent withdrawal. Imaging was conducted Q8W in year 1 and Q12W thereafter. Planned sample sizes were 23 pts for NIVO and 40 pts for NIVO + IPI. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS). Results: 68 pts received NIVO (n = 25) or NIVO + IPI (n = 43) with ≥ 24 m follow-up (median: NIVO, 62.5 m; NIVO + IPI, 24.4 m). In the NIVO arm, median age was 66 yrs (range, 27–88), 10 (40.0%) pts had ECOG PS of 1, and 15 (60.0%) were treatment-naive. In the NIVO + IPI arm, median age was 70 yrs (range, 48–85), 27 (62.8%) pts had ECOG PS of 1, and 33 (76.7%) were treatment-naive. Treatment duration was 15.8 m in the NIVO arm, and 7.9 m for NIVO and 6.0 m for IPI in the NIVO + IPI arm. Efficacy and safety outcomes are summarized in the table. ORR was 60.0% (95% CI, 38.7–78.9) in the NIVO arm and 58.1% (95% CI, 42.1–73.0) in the NIVO + IPI arm. The most common reasons for treatment discontinuation were disease progression (NIVO, 28.0%; NIVO + IPI, 32.6%) or study-drug toxicity (NIVO, 20.0%; NIVO + IPI, 25.6%). There was 1 study drug-related death in each arm (NIVO, pneumonitis; NIVO + IPI, gastrointestinal motility disorder). Conclusions: Both NIVO and NIVO + IPI show durable clinical efficacy in advanced MCC. While the non-randomized trial design limits comparisons between the arms, results do not suggest additional efficacy benefit with IPI added to NIVO. Higher incidence of grade 3/4 TRAEs observed in the combination arm could have resulted in shorter treatment duration. Clinical trial information: NCT02488759 . [Table: see text]
Towards organ preservation and cure via 2 infusions of immunotherapy only, in patients normally undergoing extensive and mutilating curative surgery for cutaneous squamous cell carcinoma: An investigator-initiated randomized phase II trial—The MATISSE trial.
Authors: Zuur Charlotte L. , Breukers Sabine , Machuca-Ostos Mercedes , Boere Thomas , Smit Laura , De Boer J.P. , Cornelissen Sten , Navran Arash , van Houdt Winan J. , Westerink Bram , Wondergem Maurits , de Bree Remco , Devriese Lot A. , Thommen Daniela , Traets Joleen , Haanen John B. A. G.
Published: June 2023

9507

Background: Standard of care for locally advanced cutaneous SCC (CSCC) consists of extensive and mutilating surgery often with adjuvant radiotherapy (RT). To improve clinical prospects of these patients (pts), we tested efficacy of neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (COMBO) in pts with CSCC with an indication for extensive surgery with or without adjuvant RT. Methods: 40 pts with T1-4N0-3M0 or TxN1-3M0 CSCC and an indication for extensive and/or mutilating surgery were needed to reach the primary objective of this trial. Pts were randomized for ARM A: NIVO (3 mg/kg, weeks 0&2, N = 26) or ARM B: NIVO (3 mg/kg, weeks 0&2) + IPI (1mg/kg, week 0, N = 24) prior to surgery (week 4). Primary objective was pathological response at time of surgery. A major pathological response (MPR) was defined as ≤10% residual viable cancer cells in the surgical resection specimen. Secondary endpoints were tolerability (CTCAE v.5.0), survival, and quality of life (QOL). Key exploratory aim for the trial was the serial collection of pre- and on-treatment tumor samples to investigate immunogenomic features correlating with immunotherapy response. Preliminary results: 50 pts were enrolled at median age 76, of whom 32% with TxN1-3M0 disease. Grade 3-4 irAEs occurred in 6 (12%) pts and were well manageable. 40 pts underwent standard of care surgery w/wo adjuvant RT, of whom 40% and 53% reached an MPR upon NIVO and COMBO, respectively. However, 10 pts withdrew consent to undergo surgery and RT, of whom nine pts declined because of self-reported substantial clinical remission upon neoadjuvant immunotherapy. These clinical responses were confirmed via FDG-PET evaluation in week 4. All these 9 pts are currently cancer free at median FU of 12 months (range 4 to 27) with superior QOL compared to MATISSE pts undergoing standard of care. Overall, we found deep clinical responses in 13/26 (50%) and 14/23 (61%) of pts upon NIVO and COMBO, respectively, being either a MPR at time of surgery or a clinical CR in patients declining surgery. Preliminary conclusions: The MATISSE trial shows deep responses of 50% and 61% upon neoadjuvant NIVO and COMBO, respectively, with well manageable toxicity in this elderly CSCC population. Nine MATISSE patients have proven the concept that organ preservation and durable complete remissions can be achieved after two infusions of neoadjuvant immunotherapy only, without extensive or mutilating curative surgery and/or RT. Clinical trial information: NCT04620200 .
Temozolomide plus cisplatin versus toripalimab (anti-PD-1) as adjuvant therapy in resected mucosal melanoma.
Authors: Lian Bin , Tian Hui , Si Lu , Chi Zhihong , Sheng Xinan , Wang Xuan , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Wei Xiaoting , Li Juan , Li Caili , Cui Chuanliang , Guo Jun
Published: June 2023

9508

Background: Chemotherapy (temozolomide plus cisplatin) has been demonstrated to be a better adjuvant regimen compared to high-dose interferon alpha-2b in resected Mucosal Melanoma (MuM) in the pre-immunotherapy era. Yet in the present immunotherapy era, PD-1 inhibitor was recommended as a standard adjuvant therapy for resected Melanoma. No adjuvant trial comparing chemotherapy with PD-1 inhibitor in resected MuM had been reported. we conducted this study to determine the efficacies of adjuvant chemotherapy versus PD-1 inhibitor in resected MuM. Methods: All patients (pts) with resected MuM received chemotherapy (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or Toripalimab (anti-PD-1, 3 mg/kg every 2 weeks via intravenous infusion) as adjuvant therapy from 2013 to 2019 were included retrospectively. Demographic and clinical characteristics between the two groups were matched with 1:1 by propensity score matching (PSM) to reduce the bias. After PSM, the efficacies of the two groups were compared, and subgroup analysis was performed according to the baseline characteristics. The endpoints were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Kaplan-Meier methods and Cox regressions were used to estimate median RFS, DMFS, OS and HR. Results: A total of 247 pts were included, of which 78 were in the Toripalimab group and 169 were in the Chemo group. PSM matched 65 pts from each of the two groups. The baseline characteristics were similar. At a median follow-up of 52.6 months (95%CI, 44.6-60.6 months), patients receiving chemo had a longer median RFS (28.2 vs. 12.0 months; HR=0.64, 95% CI, 0.42 to 0.98; P=0.04), DMFS (42.0 vs. 19.0 months; HR=0.58, 95% CI, 0.36 to 0.92; P=0.02) and OS (93.4 vs. 39.3 months; HR=0.56, 95% CI, 0.33 to 0.94; P=0.03) versus the toripalimab group (Table). Conclusions: Adjuvant chemotherapy (temozolomide plus cisplatin) shows remarkable longer RFS, DMFS, and OS than Toripalimab (anti-PD-1). It suggested that adjuvant chemotherapy may be a better option for patients with resected mucosal melanoma even in the present immunotherapy era. [Table: see text]
Initial efficacy and safety of RP1 + nivolumab in patients with anti–PD-1–failed melanoma from the ongoing phase 1/2 IGNYTE study.
Authors: Chmielowski Bartosz , Milhem Mohammed M. , Sacco Joseph J. , Bowles Tawnya Lynn , Tsai Katy K. , In Gino Kim , Muñoz-Couselo Eva , Vanderwalde Ari M. , Chesney Jason Alan , Michels Judith , Samson Adel , Beasley Georgia , Schadendorf Dirk , Mahmoud Fade , Wong Michael K.K. , Wise-Draper Trisha Michel , Zhu Junhong , Bommareddy Praveen , Hou Jeannie W. , Middleton Mark R.
Published: June 2023

9509

Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from the first 75 pts enrolled into the registration-directed (R-D) cohort in anti–PD-1–failed melanoma (target enrollment N = 125) from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts must have locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) on 2 assessments ≥28 days apart while on ≥8 consecutive weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy must have had PD confirmed by biopsy while on adjuvant therapy. RP1 is initially given intratumorally at 106 PFU/mL and then every 2 weeks (Q2W) at 107 PFU/mL for ≤8 total cycles (≤10 mL/dose) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then receive nivo alone (240 mg Q2W or 480 mg Q4W IV) for ≤2 years, with the option to reinitiate RP1 if specified criteria are met. Results: A total of 91 pts are included in this analysis (initial melanoma cohort, 16 pts; R-D cohort, 75 pts; data cut: Dec 30, 2022). The overall objective response rate (ORR) was 37.4% (initial cohort, 37.5%; R-D cohort, 37.3%) and 18.7% of pts achieved complete response (CR; Table). The response rates seen were also encouraging when evaluated by prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions in most responding patients, including in pts with bulky and visceral disease. The majority of responses were observed in pts with PD-L1–negative tumors at baseline (17 of 52 pts with PD-L1–negative tumors responded, compared to 15 of 26 pts with PD-L1–positive tumors, and 2 of 13 pts for whom PD-L1 status was unknown). 85.3% of responses were ongoing 3.7–36.6 months from initiating therapy. Most treatment-related adverse events (TRAEs) were Grade 1–2 with the most common (>20%) being fatigue, chills, pyrexia, and nausea. Conclusions: The initial data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated, with mostly on-target TRAEs. Additional and updated data will be presented. Clinical trial information: NCT03767348 . [Table: see text]
NeoPlus: A phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma.
Authors: Mao Lili , Si Lu , Dai Jie , Bai Xue , Li Caili , Wei Xiaoting , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Tang Bixia , Lian Bin , Wang Xuan , Yan Xieqiao , Zhou Li , Kong Yan , Wu Xiaowen , Li Siming , Li Juan , Guo Jun
Published: June 2023

9514

Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, ongoing phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566 .
The validity of a machine learning algorithm in predicting response to immune checkpoint inhibitors in melanoma.
Authors: Fa'ak Faisal , Coudray Nicolas , Jour George , Goldberg Clara , Johannet Paul , Huang Alexander Chan Chi , Mitchell Tara , Xu Xiaowei , Tsirigos Aristotelis , Weber Jeffrey S. , Osman Iman
Published: June 2023

9523

Background: We previously reported the development of a machine learning algorithm to predict immunotherapy response in patients with advanced melanoma using retrospectively collected pretreatment histologic slides (Johannet et al, CCR 2021). In this study, we tested the validity of the same algorithm in two independent cohorts of melanoma patients enrolled in phase III clinical trials of immune checkpoint inhibitors (ICI), one metastatic, and one adjuvant. Methods: We examined 336 patients enrolled in CheckMate 067(NCT01844505) and CheckMate 238 (NCT02388906). We used deep convolutional neural networks (DCNN) to automatically segment images into three regions of interest: tumor, lymphocytes, and stroma. The algorithm was previously trained and tested to predict the complete and partial response (CR/PR) versus progression of disease (POD) and to predict the probability of progression-free survival (PFS) while on ICI. We tested the performance in the two cohorts; the first (CheckMate 067) included 164 patients with stage III/IV unresectable melanoma who received ipilimumab (n= 49), nivolumab (n = 59), or combination (n= 56) therapy as a first line, then tested whether the algorithm could perform as well in the second cohort (CheckMate 238) which included 172 patients with stage III/IV resectable melanoma who received adjuvant ipilimumab (n = 87) or nivolumab (n = 85) therapy as first line. Results: The segmentation classifier identified tumor within slides with an area under the curve (AUC) of 0.99. A combined model of DCCN and treatment predicted POD with an AUC of 0.72 in metastatic melanoma patients enrolled in Checkmate 067. The DCCN classified patients into high and low risk based on their likelihood of PFS (P <0.0001). However, the same algorithm is not effective in predicting recurrence in patients treated in the adjuvant setting in Checkmate 238 (AUC 0.52). Retraining and testing using only patients treated in the adjuvant setting improved the AUC average to 0.65-0.70. Conclusions: Our results show the reproducibility of our previously developed algorithm in predicting response in patients with advanced metastatic melanoma. The inability of the model to predict recurrence in patients treated in the adjuvant setting might reflect the difference in the endpoint tested (response versus recurrence), which requires further training on larger datasets for this particular endpoint prediction, and/or the limited tumor volume in resected disease below a threshold that machine learning can predict a difference.
Economic evaluation for the US of relatlimab and nivolumab (RELA+NIVO) versus nivolumab (NIVO) monotherapy in untreated advanced melanoma.
Authors: Aqel Osama , Alfayoumi Ibrahim , Shen Yunrong , Aliu Oiza , Zaidi Syeda Hina , Moreno-Rodriguez Valeria , Ayoade Oluwayemisi O , Alzahir Hassan , Kopecky Jan Marco , Khattab Salma , Snyder Mattie , Abraham Ivo
Published: June 2023

9539

Background: The RELATIVITY-047 trial demonstrated longer median progression-free survival (PFS) with the combination of RELA+NIVO (10.1 months, 95% CI = 6.4 to 15.7) over NIVO (4.6 months, 95%CI = 3.4 to 5.6) in patients with untreated advanced melanoma (hazard ratio for progression or death = 0.75, 95%CI = 0.62 to 0.92). This economic evaluation aimed to estimate the cost-effectiveness/utility of RELA+NIVO vs. NIVO monotherapy in this setting. Methods: A two state partitioned survival model (PFS, progressed/death) was developed to compare costs and PFS outcome associated with both treatments. PFS curves were digitized and parametric functions fitted. A 5-year time horizon from a US payer perspective with a 3% discount rate/year was considered. Costs of treatment (average sales price), administration and monitoring parameters were derived from Centers for Medicare & Medicaid Services databases; cost of adverse events (grade 3/4 with rate >5%) were derived from prior advanced melanoma economic evaluations. Incremental costs, PFS life years (PFSLY), and PFS quality adjusted life years (PFSQALY) gained (g) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). A cost-effectiveness acceptability curve (CEAC) was plotted to determine the probability of either treatment to be cost-effective over the other at different willingness to pay (WTP) thresholds. Results: Exponential regression was used to extrapolate RELA+NIVO and NIVO survival curves. According to the result table shown below, the BCA (PSA) shows an incremental cost of RELA+NIVO over NIVO of $405,663 ($402,936), incremental PFSLY of 0.326 (0.325), and incremental PFSQALY of 0.260 (0.256). The BCA (PSA) ICERs indicated an additional $1,244,365 ($1,239,803) per PFSLY gained (g) and an additional $1,560,242 ($1,573,969) per PFSQALYg. The CEAC curve shows that RELA+NIVO treatment had a 50% probability of being cost-effective regimen at a WTP threshold value of $1,525,000 and 100% probability at a threshold of $3,050,000 or above. Conclusions: In the setting of advanced melanoma, this economic evaluation showed that RELA+NIVO is associated with improvement in LY and QALY, however, at a marked incremental cost, requiring a very high WTP threshold. [Table: see text]
Updated safety and efficacy results from the phase I study of either LBL-007 (an anti-LAG-3 antibody) in combination with toripalimab (an anti-PD-1 antibody) or LBL-007 in combination with toripalimab and axitinib in patients with advanced melanoma.
Authors: Bai Xue , Li Mei , Chen Yu , Si Lu , Chen Jing , Pu Xingxiang , Cheng Ying , Zou Zhengyun , Zhao Shiwei , Li Tao , Cai Shengli , Guo Jun
Published: June 2023

9541

Background: Initial safety and efficacy data of LBL-007 plus toripalimab in patients with advanced melanoma (Part A) have been reported in 2022 ASCO (Abstract 9538). Here we present the updated results of part A and the preliminary results of part B (LBL-007 plus toripalimab with axitinib). Median follow-up was 9.7 months at cut-off data (January 11, 2023). Methods: Patients with advanced melanoma with or without prior therapy were enrolled during Jan 2021 - Aug 2022. This trial comprised 2 parts: Part A, patients received LBL-007 (0.25 - 10 mg/kg for dose escalation; 3 or 6 mg/kg for dose expansion) plus toripalimab at 3 mg/kg (both i.v. Q2W); and Part B, patients received LBL-007 at 3 or 6 mg/kg plus toripalimab at 3 mg/kg (both i.v. Q2W) and axitinib at 5 mg BID. The primary objective was safety, the second objectives were pharmacokinetics, pharmacodynamics and efficacy (per RECIST v.1.1). Results: In part A, 68 patients in total (57 treatment-naïve) were enrolled including 20 patients in dose escalation and 48 patients in dose expansion, and among which, 31 additional patients have been enrolled since 2022 ASCO report. Nineteen (27.9%) patients occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs was anaemia (11.8%). No new safety signals were detected. Among 55 efficacy evaluable treatment-naïve patients (41 with acral, 7 mucosal, 7 others), ORR was 23.6%, DCR was 58.2%, and mPFS was 5.7 months (95% CI: 3.7, 9.5). In part B, 11 patients (10 mucosal, 1 acral) were enrolled. No DLT was observed. Five patients (45.5%) occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs included blood pressure increased (18.2%) and transaminases increased (18.2%). One (9.1%) patient discontinued treatment due to TEAEs. ORR was 45.4% (including 4 mucosal and 1 acral), DCR was 72.7%, and mPFS was 5.5 months (95% CI: 1.8, 9.1). Conclusions: LBL-007 plus toripalimab continued to show promising antitumor activity and manageable safety profile in patients with treatment-naïve melanoma, which support further development in this indication. LBL-007/toripalimab/axitinib combination demonstrated acceptable safety profile and encouraging antitumor activity in patients with mucosal melanoma. Acknowledgements: Junshi Biosciences. Clinical trial information: NCT04640545 .