bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated survival with extended follow-up on patients with newly diagnosed multiple myeloma treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy and a risk-stratified maintenance approach.
Authors: Parikh Rujul H , Hofmeister Craig C. , Almaula Dhwani , Heffner Leonard T. , Gupta Vikas Anand , Boise Lawrence , Kaufman Jonathan L. , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Joseph Nisha
Published: June 2022

8061

Background: Lenalidomide, bortezomib, and dexamethasone (RVD) has been established as an effective and well-tolerated induction regimen in patients with newly diagnosed myeloma (NDMM). We have previously published a retrospective analysis of 1000 patients treated with RVD and risk-stratified maintenance therapy showing a median PFS of 65 months and median OS of 126 months for the entire cohort (Joseph et al, JCO 2020). This data has served as an important benchmark for evaluating upfront treatment strategies in NDMM. Here, we present updated survival data with extended follow up on this patient population treated at the Winship Cancer Institute of Emory University. Methods: From January 2007 to August 2016, 1000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy (R-25 mg/day on days 1-14, V-1.3 mg/m2 on days 1,4,8,11 and D-40 mg once/twice weekly as tolerated) were identified. Demographics, clinical characteristics, and outcomes data for the patients were obtained from our institutional review board-approved myeloma database. Responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 (range 16-83). Other notable patient characteristics include: M/F 54.6%/45.4%, W/AA 61.8%/35.9%; ISS I/II/III 45.8%/30.8%/23.4%. R-ISS I/II/III 39.9%/48.7%/11.5%; Isotype IgG/IgA/FLC 59.2%/19.0%/15.7%; standard risk(SR)/high risk (HR) 71.2%/15.8%.. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype by conventional metaphase cytogenetics. 81.8% of patients underwent ASCT, with 16.8% having deferred ASCT. 75.3% of patients were initiated on maintenance therapy. With a median follow up of 88.4 months, the median PFS for the entire cohort was 68.7 months (95% CI 61.8-75.5) and the median OS was 128.9 months. The median PFS for HR patients was 42.4 months (95% CI 35.7-48.9), and the median PFS for SR patients was 80.3 months (95% CI 72.8-87.8). The median OS for SR patients was not reached, and for HR patients was 86.6 months (95% CI 70.1-103.1). Conclusions: Updated analysis with long-term follow up of this database of 1000 NDMM patients treated with RVD continues to demonstrate that, in combination with a risk-stratified maintenance strategy, RVD delivers durable remissions and impressive long-term outcomes. This study remains the largest cohort of patients treated with RVD reported to date, and continues to show the efficacy of this upfront treatment approach in newly diagnosed myeloma.
Distinct genomic and immunophenotypic features of solid-predominant versus nonsolid-predominant stage I lung adenocarcinomas and association with disease recurrence after surgical resection.
Authors: Alessi Joao Victor Machado , Wei Zihan , Ricciuti Biagio , Vaz Victor R. , Barrichello Adriana Paula de Castro , Lamberti Giuseppe , Sharma Bijaya , Pfaff Kathleen L. , Felt Kristen , Turner Madison M. , Rodig Scott J. , Sholl Lynette M. , Awad Mark M.
Published: June 2022

8514

Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAFV600E, and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P < 0.001), no difference in KRASG12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P < 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P < 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P < 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P < 0.001) and at the tumor-stroma interface (P < 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.
Sintilimab plus anlotinib as second or further-line therapy for small cell lung cancer: An objective performance trial.
Authors: Ma Shuxiang , He Zhen , Wang Lili , Wu Yufeng , Yang Sen , Chen Haiyang , Wu Yingxi , Mo Yuqing , Liu Yang , Wang Qiming
Published: June 2022

8516

Background: Small cell lung cancer (SCLC) tends to progress rapidly on first-line therapies, with limited subsequent-line treatment options. Methods: In this single-arm objective performance trial, adult patients with extensive-disease SCLC (ED-SCLC) received intravenous sintilimab 200 mg on day 1 and oral anlotinib 12 mg on days 1-14. Treatment lasted for 3 weeks per cycle and was continued until disease progression, unacceptable toxicities, or death. The primary endpoint was the superiority of progression-free survival (PFS) versus a PFS of 2.8 months with historical topotecan control. Results: Forty-two patients were enrolled, and 39 patients were evaluable for efficacy. Twenty-six patients (66.7%) had ED-SCLC, and 13 (33.3%) relapsed after concurrent chemoradiotherapy. The median follow-up was 11.9 months. The median PFS was 6.0 months (95%CI: 4.8-7.2). The 6- and 12-month PFS rate was 50.5% and 27.8%, respectively. Fourteen patients died by the data cut-off date, and overall survival (OS) was immature (16.1 months, 95%CI: 9.4-22.7). The 12- and 18-month OS rate was 56.7% and 42.5%, respectively. Three patients attained complete response and 16 achieved partial response, and 12 patients had stable disease; the objective response rate was 48.7% and the disease control rate was 79.5%. Forty patients (95.2%) had at least one treatment-related adverse event (TRAE). The most frequent TRAEs were hypothyroidism (45.2%), hypoproteinemia (40.5%) and elevated gamma-glutamyl transpeptidase (38.1%). Conclusions: Immunotherapy with sintilimab plus antiangiogenic drug anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further development of this combination regimen for ED-SCLC. Clinical trial information: NCT04055792.
Analysis of patients with relapsed small cell lung cancer (SCLC) receiving single-agent lurbinectedin in the phase 3 ATLANTIS trial.
Authors: Navarro Alejandro , Ponce Aix Santiago , Barneto - Aranda Isidoro C. , Smit Egbert F. , Lopez-Vilariño Jose Antonio , Nieto Antonio , Kahatt Carmen Maria , Zeaiter Ali Hassan , Cousin Sophie , Bischoff Helge , Roubec Jaromir , Syrigos Konstantinos , Paz-Ares Luis
Published: June 2022

8524

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, received accelerated approval from the US FDA in June 2020 as monotherapy (3.2 mg/m2 IV every 21 days) for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. This approval was based on the overall response rate (35.2%) and duration of response (DOR; 5.3 months) observed in 105 patients from a phase 2 trial. The ATLANTIS trial (NCT02566993) investigated the combination of lurbinectedin 2.0 mg/m2 IV + doxorubicin (DOX) 40.0 mg/m2 IV versus topotecan or CAV. This post hoc analysis explored the efficacy and safety of single-agent lurbinectedin in patients who completed 10 cycles of the combination and then switched to lurbinectedin monotherapy per protocol. Methods: Eligible patients were ≥18 years of age with limited-stage or extensive-stage SCLC, 1 prior line of platinum-based chemotherapy (PD-1/PD-L1 inhibitors were also permitted), ECOG PS ≤2, and chemotherapy-free interval ≥30 days. Tumor assessments were per an independent review committee (IRC). Results: Patients who completed 10 cycles of lurbinectedin + DOX and switched to lurbinectedin monotherapy (n = 50) had a median age of 61.5 years (range: 43, 77); 62% were male; and 100% had an ECOG PS < 2. The overall median number of cycles was 15 (range: 11, 47) and included a median of 5 (1, 37) cycles on monotherapy. The majority of patients who switched to lurbinectedin monotherapy maintained or improved their tumor response (Table). All 3 patients who achieved a complete response (CR) on combination therapy maintained their CR on monotherapy. Of the 26 patients with a partial response (PR) on combination therapy, 3 (12%) achieved a CR and 15 (58%) maintained their PR. Of the 19 patients with stable disease (SD) on combination therapy, 3 (16%) improved from SD to PR (n = 2) or CR (n = 1) and 8 (42%) maintained SD. The median DOR was 8.3 months (95% CI: 7.1, 11.0). The median overall survival (OS) was 20.7 months (95% CI: 15.7, 24.8). Grade 3/4 hematologic abnormalities based on laboratory assessment included lymphopenia (36%), anemia (16%), thrombocytopenia (12%), neutropenia (12%), and leukopenia (10%). Febrile neutropenia was reported in 4% of patients. Conclusions: Patients with relapsed SCLC in ATLANTIS who completed 10 cycles of lurbinectedin + DOX combination and switched to lurbinectedin monotherapy tended to maintain or improve their tumor response (including an increase in CRs), with favorable OS and DOR and acceptable tolerability with no new safety signals. Clinical trial information: NCT02566993. [Table: see text]
Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: Updated results from the CHRYSALIS study.
Authors: Krebs Matthew , Spira Alexander I. , Cho Byoung Chul , Besse Benjamin , Goldman Jonathan W. , Janne Pasi A. , Ma Zhiyong , Mansfield Aaron Scott , Minchom Anna Rachel , Ou Sai-Hong Ignatius , Salgia Ravi , Wang Zhijie , Llacer Perez Casilda , Gao Grace , Curtin Joshua C , Roshak Amy , Schnepp Robert W. , Thayu Meena , Knoblauch Roland , Lee Chee Khoon
Published: June 2022

9008

Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]
Sintilimab versus pembrolizumab in monotherapy or combination with chemotherapy as first-line therapy for advanced non–small cell lung cancer: Results from phase 2, randomized clinical trial (CTONG1901).
Authors: Liu Si-Yang Maggie , Zhou Qing , Yan Hong-Hong , Bin Gan , Yang Ming-Yi , Deng Jia-Yi , Tu Hai-Yan , Zhang Xuchao , Su Jian , Yang Jinji , Wu Yi-Long
Published: June 2022

9032

Background: Immunotherapy has become standard therapy for untreated advanced NSCLC. However, no direct comparison between anti-PD-1 inhibitors has been reported. Methods: CTONG1901 is an open label, randomized, phase II clinical trial to compare sintilimab and pembrolizumab in monotherapy or combination with chemotherapy for advanced NSCLC at first-line setting. The primary endpoint was objective response rate (ORR). Patient without EGFR and ALK alteration were enrolled. Patients with PD-L1 tumor proportion score (TPS) ≥50% were randomly to receive sintilimab (A) or pembrolizumab (B) ; and with TPS<50% were randomly to receive sintilimab (C) or pembrolizumab (D) combined with chemotherapy. Sample size was calculated by Optimal Two-Stage Designs. 20 patients were enrolled in 1st stage. When ≥4 patients achieve partial response (PR) in sintilimab arms, the study will enter into 2nd stage and the sample size will be calculated based on the ORR results of the 1st stage. Results: The ORR was 57.1% in sintilimab and 33.3% in pembrolizumab arms at the 1st stage. The study successfully entered into the 2nd stage. 48 additional patients should be enrolled after calculation. When 15 PR in sintilimab arms achieved, the primary endpoint will be reached. From Mar. 2020 to Jan. 2022, 71 patients were screened and 68 patients were enrolled in two stages. Histologic subtypes and brain metastasis were well balanced between arms. As of Dec. 31st 2021, the median follow-up was 5.6 months. The confirmed ORR was 45.5% (15/33) in sintilimab vs. 28.6% (10/35) in pembrolizumab arms (A vs. B: 30.8% [4/13] vs. 28.6% [4/14]; C vs. D: 55.0% [11/20] vs. 28.6% [6/21]). Unconfirmed ORR was 57.6% vs. 42.9% and disease control rate (DCR) was 87.9% vs. 91.4% in sintilimab and pembrolizumab arms. The primary endpoint was reached. Survival data was immature. Any grade and 3-4 grade treatment-related adverse events (TRAEs) were comparable in sintilimab and pembrolizumab arms (Table). Conclusions: This is the first head-to-head phase II study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. The result suggested comparable tumor response and similar safety profile between sintilimab and pembrolizumab. Clinical trial information: NCT04252365. [Table: see text]
Outcomes of single-agent PD-(L)-1 versus combination with chemotherapy in patients with PD-L1-high (≥ 50%) lung cancer.
Authors: Elkrief Arielle , Alessi Joao Victor Machado , Ricciuti Biagio , Rizvi Hira , Preeshagul Isabel Ruth , Egger Jacklynn V. , Chaft Jamie E. , Rudin Charles M. , Riely Gregory J. , Kris Mark G. , Ladanyi Marc , Hellmann Matthew D. , Awad Mark M. , Schoenfeld Adam Jacob
Published: June 2022

9052

Background: Single agent PD-(L)-1 blockade (IO) and PD-(L)-1 blockade combined with chemotherapy (ChemoIO) are both standard first-line treatments for patients with PD-L1-high (≥ 50%) metastatic non-small cell lung cancer (NSCLC). These regimens have not been compared prospectively, so comparative effectiveness is unclear. It is also unknown if clinical and molecular tumor characteristics differentially associate with benefit to IO vs ChemoIO in patients with NSCLC with high PD-L1 tumor expression. Methods: All patients with metastatic NSCLC treated with IO or ChemoIO at two institutions (Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute) were reviewed. Patients with EGFR or ALK alterations, PD-L1 expression < 50%, treated with IO or ChemoIO in > 1st line setting were excluded. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the IO vs ChemoIO groups and association with clinical, pathologic, and molecular features was examined. To account for NGS panel differences, tumor mutational burden (TMB) values were harmonized using a z-score conversion as previously described (Vokes et al, 2019). Results: Of 639 patients with stage IV EGFR/ ALK wild-type NSCLC and PD-L1 ≥50% treated in the 1st line setting, 504 received IO and 135 received ChemoIO. Baseline ECOG performance status (p = 0.3), median PD-L1 % (p > 0.9) and TMB (p = 0.2) were similar between the IO and ChemoIO groups. For patients receiving IO vs ChemoIO, there was no significant difference in OS (HR 0.8, 95% CI 0.6 to 1.08; p = 0.2). Median PFS was shorter (HR 0.7, 95% CI 0.6 to 0.9; p = 0.004) and ORR was lower (40% IO vs 55% ChemoIO, p = 0.002) in the IO group. Among patients with durable responses (> 6 months), never smokers were less common in the IO group (6% vs 18%, p < 0.001), but there was no difference in PD-L1 expression, TMB, or mutational ( KRAS, STK11, or KEAP1) profile to suggest differential predictors of benefit to IO or ChemoIO. Conclusions: In patients with PD-L1 high NSCLC, there was no survival benefit associated with the addition of chemotherapy to IO. There were also no clear differences in PD-L1 expression or molecular features associated with durable response to IO vs ChemoIO. These findings have implications for treatment selection in this population.
SAF-189s in advanced, ALK-positive, non–small cell lung cancer: Results from a first-in-human phase 1/2, multicenter study.
Authors: Yang Jin-Ji , Zhou Jianying , Cheng Ying , Li Mingjun , Zhao Qiong , Zhang Zhiye , Zang Aimin , Fan Yun , Hui Ai-Min , Zhou Yongchu , Wu Zhuli , Sun Juan , Pan Zhaoyang , Qiu Jingjun , Wu Yi-Long
Published: June 2022

9076

Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]
BRAF mutation classes and co-occurring mutations in NSCLC.
Authors: Niu Jiaxin , Flannery Cynthia A. , Hall David W. , Hoag Jess W. , Therala Nishitha , Kemkes Ariane C. , Routh Josh , De La O Jean-Paul , Macera Lisa , Thakkar Snehal Govind
Published: June 2022

9083

Background: Targeted therapy against unique molecular drivers has revolutionized non-small cell lung cancer (NSCLC) treatment. BRAF mutations, present in 2%-5%, have emerged as therapeutic targets, and can be divided into three classes: kinase-activating monomers (class I, V600) or dimers (class II), or kinase-inactivating dimers (class III). Most studies have focused on BRAF V600E NSCLC. Limited clinical data suggest classes II and III may not respond well to chemo- or targeted therapy and tend to have a poorer prognosis. Little is known about co-occurring mutations. This study examines BRAF classes and co-occurring mutations in NSCLC. Methods: Between October 2018 and October 2021, data from 3009 NSCLC Oncotype MAP test results were analyzed. This test utilizes tumor DNA to identify single nucleotide variants, indels, copy number alterations, and select structural variants/fusions by next generation sequencing with a 257 gene panel. Tumor mutational burden and microsatellite instability are also assessed. Pathogenic/likely pathogenic mutations were identified, BRAF mutations assigned to 3 different classes based on current understanding, and associations of other mutated genes with BRAF class examined. Results: Among samples, 133 (4.4%) had BRAF mutations: 30 class I (1%); 42 class II (1.4%); 36 class III (1.2%); and 25 unclassified (0.8%) (Table). Two genes showed associations with BRAF class: STK11 was significantly overrepresented in class II and III, and SETD2 in class I (p<0.05 for both). BRAF class II mutations were further divided into subclasses, IIa (n= 5) and IIb (n= 35); two could not be assigned. The lack of a positive association between KRAS (and NF1) and BRAF class III was unexpected since class III is RAS-dependent while class I and II are RAS-independent. The overrepresentation of STK11 in classes II (with 11/12 events in IIb) and III might explain, at least in part, the poor prognosis relative to class I. By contrast, SETD2 is overrepresented in class I, which might help explain its better response to immunotherapy. Conclusions: For the first time we report the incidence of BRAF mutation classes and associated co-mutations in NSCLC. These associations may help to explain therapeutic outcomes. The impact of coexisting STK11 mutations in class II subclasses warrants further investigation.[Table: see text]
Results of a phase 1b study of osimertinib plus sapanisertib or alisertib for osimertinib-resistant, EGFR-mutant non–small cell lung cancer (NSCLC).
Authors: Elamin Yasir Y , Negrao Marcelo Vailati , Fossella Frank V. , Byers Lauren Averett , Zhang Jianjun , Gay Carl Michael , Tu Janet Chen , Pozadzides Jenny Vu , Tran Hai T. , Lu Charles , Feng Lei , Spelman Amy R. , Blumenschein George R. , Tsao Anne S. , Heymach John
Published: June 2022

9105

Background: The aurora kinase and mTOR pathways are implicated in resistance to EGFR inhibitor osimertinib. Here, we investigated the safety and efficacy of the aurora kinase inhibitor alisertib and the mTOR inhibitor sapanisertib in combination with osimertinib. Methods: This is a phase 1b study with dose finding and expansion portions (NCT04479306). The dose finding portion used a Bayesian optimal interval (BOIN) design to assess two arms: osimertinib 80 mg daily in combination with alisertib 20 mg, 30 mg, and 40 mg daily day 1-21 of 28-day cycle (osi-ali arm) and osimertinib 80 mg daily in combination with sapanisertib 2 mg and 3 mg daily (osi-sapa arm). Dose limiting toxicities (DLTs) were predefined in the protocol. Patients with EGFR (L858R/exon 19 deletion) mutant NSCLC whose disease have progressed on osi and up to one additional line of systemic therapy were assigned, at investigator discretion, to either study arm. Tumor biopsy was mandatory at study entry and optional upon progression. Results: As of February 1, 2022, 40 patients are enrolled (20 in each arm). One DLT was observed in each arm: grade 3 nausea in ali-osi arm and grade 3 AST elevation in osi-sapa arm. Grade 3 treatment emergent adverse events (TEAEs) occurred in 10% of each arm, and no grade 4 TEAEs were observed. The most common TEAEs in osi-ali arm was leucopenia (45%) and anemia (35%) while in osi-sapa arm, hyperglycemia (45%) and stomatitis (40%). In osi-ali arm (n = 20), median progression free survival (mPFS) was 1.9 months while objective response rate (ORR) and disease control rate (DCR) were 5% (95% CI: 0.1 ̃ 24.9%) and 40% (95% CI: 19.1 ̃ 63.9%), respectively. In osi-sapa arm (n = 16, evaluated for response to date), mPFS was 4.6 months while ORR and DCR were 12.5% (95% CI: 1.6 ̃ 38.3%) and 68.7% (95% CI: 35.7 ̃ 82.7%), respectively. Conclusions: Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib. Clinical trial information: NCT04479306.
Nivolumab (NIVO) + relatlimab (RELA) versus NIVO in previously untreated metastatic or unresectable melanoma: OS and ORR by key subgroups from RELATIVITY-047.
Authors: Tawbi Hussein A. , Hodi F. Stephen , Lipson Evan J. , Schadendorf Dirk , Ascierto Paolo Antonio , Matamala Luis , Salman Pamela , Gutiérrez Erika Castillo , Rutkowski Piotr , Gogas Helen , Lao Christopher D. , Janoski De Menezes Juliana , Dalle Stéphane , Arance Ana Maria , Grob Jean-Jacques , Keidel Sarah , Jonczak Karin , Sobiesk Anne Marie , Dolfi Sonia , Long Georgina V.
Published: June 2022

9505

Background: In the phase 2/3 RELATIVITY-047 trial, NIVO + RELA as a fixed-dose combination (FDC) significantly improved the primary endpoint of progression-free survival (PFS) versus NIVO in patients (pts) with previously untreated metastatic or unresectable melanoma. Secondary endpoints showed a clinically meaningful improvement in overall survival (OS), although not statistically significant, and a higher objective response rate (ORR). As previously reported, PFS and OS favored NIVO + RELA over NIVO across prespecified stratification factors (LAG-3 expression, PD-L1 expression, BRAF V600 mutation status, and metastasis stage). Here we report the first disclosure of ORR analyzed by prespecified stratification factors and OS and ORR in additional subgroups. Methods: Pts were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg intravenously Q4W. The primary endpoint was PFS per RECIST v1.1 assessed by blinded independent central review (BICR). Secondary endpoints were OS and ORR by BICR, tested in hierarchy. Exploratory analyses were performed for PFS, OS, and ORR by prespecified subgroups. Results: PFS continued to favor NIVO + RELA over NIVO across key subgroups. OS and ORR also favored NIVO + RELA over NIVO across key subgroups including those associated with poor prognosis (Table). ORR favored NIVO + RELA over NIVO for pts with LAG-3 expression ≥ 1% (47% vs 35%) and < 1% (31% vs 24%), PD-L1 expression ≥ 1% (53% vs 45%) and < 1% (36% vs 24%), and BRAF wild-type (43% vs 34%) and mutant (43% vs 31%) melanoma, respectively. Additional key prespecified subgroups will be presented. In all treated pts, NIVO + RELA maintained a manageable safety profile with no new or unexpected safety signals. Conclusions: NIVO + RELA was favored over NIVO across key subgroups for PFS, OS, and ORR, and findings appeared consistent with outcomes in the overall population. NIVO + RELA had a favorable benefit-risk profile. Clinical trial information: NCT03470922. [Table: see text]
First interim analysis of the SirTac trial: A randomized phase II study of SIRT and DSM-TACE in patients with liver metastases from uveal melanoma.
Authors: Peuker Caroline-Anna Anna , De Bucourt Maximilian , Gebauer Bernhard , Amthauer Holger , Erxleben Christoph , Eucker Jan , Keller Ulrich , Leyvraz Serge , Joussen Antonia M. , Keilholz Ulrich , Ochsenreither Sebastian
Published: June 2022

9511

Background: The liver is the most common site of metastases in patients (pts) with uveal melanoma (UM). Here, we present results from the prespecified first interim analysis of the SirTac trial, a prospective, single-center, randomized, investigator-initiated, open-label phase 2 study of Selective Internal Radiation Therapy with Yttrium-90-bearing resin microspheres; SIR-Spheres (SIRT) vs Transarterial Chemoembolization with Cisplatin and degradable starch microspheres; EmboCept S (DSM-TACE) in pts with liver-dominant metastatic UM. Methods: Pts with histologically confirmed, liver-dominant metastatic UM and ECOG PS 0-2 were enrolled and randomized 1:1 to SIRT or DSM-TACE. Randomization was stratified by lactate dehydrogenase (<2x vs ≥2x upper limit of normal) and pre-treatment with antiangiogenic agents. Extrahepatic metastases were allowed, if asymptomatic. Primary endpoint was progression-free survival (PFS). A total of 108 pts (54 per arm) were planned to be enrolled. Pts received TACE every 4-6 weeks until tumor devascularization or disease progression or intolerable toxicity was observed, and SIRT either as one whole-liver application or in two sequential sessions for each liver lobe. The primary objective of this prespecified analysis was to assess response by RECIST criteria v1.1 in the per-protocol (PP) population of the first 40 pts (20 pts in each arm). Results: Two patients had been treated with previous liver surgery, whereas all other patients had not received previous treatment for metastatic disease. There were no clinicopathological differences between the groups, except for a difference in age (median age SIRT arm 64 y vs 75 y in the TACE arm, p=0.018). All but 1 pt received treatment as randomized. This pt was excluded and replaced by the next TACE pt for this PP interim analysis. There were no differences in best overall response rates between the groups (no complete response, 1 partial response in both arms, stable disease in 19 (95%) and 17 (85%) pts in the SIRT and TACE arm, respectively, and 2 pts with progressive disease in the TACE arm). At a median follow-up of 13.9 mo from treatment start, median PFS in the PP population was 4.9 mo in the SIRT arm vs 2.2 mo in the TACE arm (p=0.037), with a higher median liver-PFS in the SIRT vs TACE arm (8.3 vs 2.2, p=0.026). Conclusions: In this planned interim analysis treatment in both arms was feasible with no differences in response. The explorativePFS analysis allows no conclusions on the final outcome after completion of the trial. The study continues recruitment. Clinical trial information: NCT02936388.
Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy.
Authors: Karapetyan Lilit , Karunamurthy Arivarasan , Cillo Anthony , Rohatgi Anjali , Massa Ryan Campbell , Gooding William E. , Najjar Yana G. , Davar Diwakar , Luke Jason J. , Bruno Tullia C. , Vignali Dario , Kirkwood John M.
Published: June 2022

9514

Background: A phase II study of nivo and rela was designed to evaluate the antitumor activity and mechanism of this combination and components for first-line treatment of pts with advanced melanoma. Pts received lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy. We assessed the effect of each lead-in treatment on immune-related pathological response (irPR) at 4-wk biopsy to develop early biomarkers of antitumor response. Methods: Core biopsy of an index lesion was performed at baseline and after 4 wk on-treatment. Immune characteristics of pathological response were assessed on H&E sections, including presence of tumor-infiltrating lymphocytes (TIL), neovascularization, proliferative fibrosis, plasma cells, and lymphoid aggregates. irPR score was calculated as described by Stein JE et al Ann Oncol 2019, from 0 (no irPR features) to 3 (major pathologic response on biopsy [MPRbx], ≤10% residual viable tumor). We assessed the association between irPR and radiological response (RECIST v1.1) at 4-wk evaluations. Results: The current cohort includes 22 pts, median age = 67, male = 13. Pts were randomized to nivo = 7, rela = 7, and nivo-rela = 8 lead-in groups. Two pts had no irPR evaluation due to early progression and unscorable tumor. Among 20 evaluable pts, proliferative fibrosis, neovascularization, plasma cells, brisk TIL, and lymphoid aggregates were identified in 50%, 35%, 26.3%, 25%, and 5% of cases, respectively. Lead-in nivo (n = 2/6), rela (n = 0/6), and nivo-rela (n = 3/8) resulted in irPR = 3 in 25% of pts. Radiological response was identified as partial response (PR) = 1/22 (4.5%), stable disease (SD) = 12/22 (54.5%), and progressive disease (PD) = 9/22 (41%). Among pts with PD, 44% received rela-, 33% nivo-, and 22% nivo-rela- lead-in. Pts with irPR score = 3 had radiological PR = 1, SD = 3, and PD = 1 at 4wks. No association was found between MPRbx and radiological response at 4 wks. Conclusions: Four-wk MPRbx may serve as an early biomarker of treatment response in advanced melanoma. Lead-in treatment resulted in MPRbx of 25% and was greatest with nivo-rela lead-in. Correlations between 4 wk MPRbx and later radiological responses, survival and other endpoints will be made at completion of trial accrual. Clinical trial information: NCT03743766. [Table: see text]
Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: A multicenter, open-label, single-arm phase 2 study.
Authors: Mao Lili , Fang Meiyu , Chen Yu , Bai Xue , Cao Jun , Lin Jing , Zhang Peng , Chen Ling , Xu Jiahui , Guo Jun , Si Lu
Published: June 2022

9525

Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard therapy for cutaneous melanoma but has demonstrated low efficacy in mucosal melanoma. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab as a first-line therapy in patients with advanced mucosal melanoma. Methods: This multicenter, open-label, single-arm, phase 2 study utilized a Simon’s two-stage design. Atezolizumab (fixed-dose, 1200 mg) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR), determined by the investigator per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety with adverse events summarized using NCI-CTCAE v5.0. Results: In total, 43 patients were enrolled, including 20 (46.5%) with unresectable and 23 (53.5%) with metastatic mucosal melanoma. Median follow-up was 13.4 months at data cut-off (July 30, 2021). Forty patients were evaluable for response: In stage I analysis set (n=22), the best confirmed ORR according to RECIST v1.1 was 40.9% (9/22; 95% CI 20.7-63.7), including one CR and eight PRs. The ORR in the FAS population was 45.0% (95% CI, 29.3-61.5) (1 CR, 17 PRs) and the DCR was 65.0% (95% CI, 48.3-79.4). The median PFS was 8.2 months (95% CI, 2.7-9.6), the 6- and 12-month PFS rates were 53.4% (95% CI, 36.6-67.6) and 28.1% (95% CI, 14.2-43.9), respectively. The median OS was not reached (NR) (95% CI, 14.4-NR). The 6- and 12-month OS rates were 92.5% (95% CI, 78.5-97.5) and 76.0% (95% CI, 57.1-87.5), respectively. The median DOR was 12.5 months (95% CI, 5.5-NR). Overall, 90.7% (39/43) of patients experienced treatment-related adverse events, and 25.6% (11/43) experienced grade ≥ 3 events. Conclusions: Atezolizumab in combination with bevacizumab showed promising efficacy and a manageable safety profile in patients with advanced mucosal melanoma. Research Sponsor: Shanghai Roche Pharmaceuticals Ltd., China. Clinical trial information: NCT04091217.
Anti-LAG-3 antibody LBL-007 in combination with toripalimab in patients with unresectable or metastatic melanoma: A phase Ⅰ, open-label, multicenter, dose escalation/expansion study.
Authors: Bai Xue , Li Mei , Pu Xingxiang , Cheng Ying , Chen Jing , Jiang Yu , Chen Xue , Liu Jingjing , Fan Li , Guo Jun , Si Lu
Published: June 2022

9538

Background: LBL007 is a novel, fully human IgG4 monoclonal antibody targeting human Lymphocyte-activation gene3 (LAG-3). Dual inhibition of anti-programmed cell death protein 1 (PD-1) and LAG-3 is anticipated to synergistically increase immune response against tumor growth. Here we report the preliminary safety and efficacy of LBL-007 in combination with Toripalimab (an anti-PD-1 antibody has approved for treatment of melanoma in China) in patients (pts) with unresectable or metastatic melanoma. Methods: Pts with unresectable or metastatic melanoma with or without prior anti-PD-(L)1 therapy were enrolled. This trial comprised 2 parts, namely part 1 (dose escalation), pts received LBL-007 (0.25/1/3/6 mg/kg) /Toripalimab (3 mg/kg) both i.v., Q2W; and part 2 (expansion), pts received LBL-007 (3/6 mg/kg)/Toripalimab (3 mg/kg) both i.v., Q2W. The primary objective was safety, the second objectives included pharmacokinetics, pharmacodynamics and efficacy (per RECIST 1.1). Results: By Jan 2022, 37 pts (15 [40.5%] male, median age 59 [range 31-74] years, 9 pts [24.3%] with baseline LDH elevation, 18 [48.6%] with acral, 12 [32.4%] mucosal, 5 [13.5%] nonacral cutaneous, 2 [5.4%] primary site unknown) were enrolled, with 17 in part 1 and 20 in part 2. No dose-limiting toxicity was observed in part 1, and the MTD was not reached. Of all 37 pts, the most common treatment-emergent adverse events (TEAEs) included anemia (24.3%), creatine phosphokinase elevation (24.3%), hypothyroidism (21.6%), and aspartate aminotransferase elevation (21.6%). For 32 radiologically evaluable pts, ORR was 12.5%, DCR was 53.1%. In a preplanned subtype-specific analysis in anti-PD-(L)1 treatment-naïve pts, ORR was 27.3 % vs. 0%, and DCR was 81.8% vs. 50.0% in acral and mucosal melanoma subtypes, respectively. For anti-PD-(L)1-resistant pts (n = 11), DCR was 18.2%. Conclusions: LBL007/Toripalimab combination is well tolerated and promising efficacy in pts with unresectable or metastatic melanoma, especially in the acral type without prior anti-PD-(L)1 therapy. Clinical trial information: NCT04640545.
SALVO: Single-arm trial of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma.
Authors: Kottschade Lisa A. , Pond Gregory Russell , Olszanski Anthony J. , Zakharia Yousef , Domingo-Musibay Evidio , Hauke Ralph J. , Curti Brendan D. , Schober Sarah , Milhem Mohammed M. , Block Matthew Stephen , McWilliams Robert R.
Published: June 2022

9573

Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection <90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.
Analysis of the effect of systemic corticosteroids on survival from tebentafusp in a phase 3 trial of metastatic uveal melanoma.
Authors: Ikeguchi Alexandra , Sacco Joseph J. , Luke Jason J. , Evans T.R. Jeffry , Curti Brendan D. , Kim Kevin B. , Abdullah Shaad Essa , Watkins Claire , Karakuzu Ozgur , Nathan Paul D.
Published: June 2022

9584

Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.