bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-year update from KEYNOTE-799: Pembrolizumab plus concurrent chemoradiation therapy (cCRT) for unresectable, locally advanced, stage III NSCLC.
Authors: Reck Martin , Lee Ki Hyeong , Frost Nicolaj , Breder Valeriy Vladimirovich , Kowalski Dariusz , Levchenko Evgeny , Reguart Noemi , Martinez-Marti Alex , Houghton Baerin , Paoli Jean-Baptiste , Safina Sufiia , Komiya Takefumi , Sanford Amy , Liu Hong , Song Andrew J. , Keller Steven M. , Jabbour Salma K.
Published: June 2022

8508

Background: Primary analysis (database cutoff, Oct 28, 2020) of the global KEYNOTE-799 study (NCT03631784) in patients (pts) with unresectable, locally advanced stage III NSCLC, showed that pembrolizumab (pembro; anti–PD-1) plus cCRT resulted in an ORR of 70.5% in cohort A (n = 112; squamous and nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous only) and grade ≥3 pneumonitis in 9 (8.0%) and 7 (6.9%) pts, respectively. We present updated outcomes with 1 y of additional follow-up. Methods: In this nonrandomized, phase 2 study, eligible pts were aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA-C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received carboplatin AUC 6 plus paclitaxel 200 mg/m2 and pembro 200 mg for one 3-wk cycle, followed by carboplatin AUC 2 plus paclitaxel 45 mg/m2 QW for 6 wks plus 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and pembro 200 mg Q3W plus standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Results: Of 216 pts enrolled in this study, 112 in cohort A and 102 in cohort B received treatment. Median (range) time from first dose to database cutoff (Oct 18, 2021) was 30.2 (25.3–35.5) mo in cohort A and 25.4 (14.5–35.2) mo in cohort B. ORR (95% CI) was 71.4% (62.1%–79.6%) in cohort A and 75.5% (66.0%–83.5%) in cohort B. Median duration of response (DOR) and OS were not reached (NR) in both cohorts; median PFS was 30.6 mo in cohort A, and NR in cohort B (Table). ORR was 66.7% in pts with PD-L1 TPS <1% and 77.3% in pts with PD-L1 TPS ≥1% in cohort A and 78.6% and 72.5%, respectively, in cohort B. ORR was similar by histology (squamous, 72.0%; nonsquamous, 74.1%). Grade ≥3 pneumonitis occurred in 16 pts (7.5%) overall; 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Treatment-related grade ≥3 AEs occurred in 64.3% and 51.0% of pts in cohort A and B, respectively. Conclusions: With the accrual of additional responses after >2 y of follow-up, pembro plus cCRT continues to demonstrate robust and durable responses, regardless of PD-L1 TPS and tumor histology, promising survival outcome and manageable safety in pts with previously untreated, locally advanced stage III NSCLC. Clinical trial information: NCT03631784. [Table: see text]
Low skeletal muscle area and association with toxicity and hospitalization with chemotherapy in advanced non–small cell lung cancer.
Authors: Saraf Anurag , He John , Shin Kee-Young , Weiss Jakob , Chen Yu-Hui , Catalano Paul J. , Awad Mark M. , Christiani David C. , Aerts Hugo , Mak Raymond H.
Published: June 2022

8532

Background: Significant toxicity is common in the treatment of advanced non-small cell lung cancer (NSCLC) and can be associated with adverse events, such as unplanned hospitalization, and worse clinical outcomes. Baseline low skeletal muscle (SM) area is a marker of sarcopenia and has been associated with worse survival in other malignancies, but the association of SM area and toxicity in NSCLC is less studied. Methods: Patients with locally advanced or oligo-metastatic NSCLC treated with combined chemotherapy and radiotherapy with or without surgery from 2002-2013 at a single institution were reviewed. A deep-learning pipeline utilized existing pre-treatment computed tomography scans to calculate SM area at the 3rd lumbar vertebral level. Gold standard SM index (SMI) was calculated, adjusting for height, sex, and dichotomized per previously validated cutoff values. Grade 3 or higher hematologic (G3+ heme) toxicity, was assessed per NCI CTCAE v5.0, within 21-days of first chemotherapy cycle. Hospital use was defined as unplanned ED visit or inpatient hospitalization during chemotherapy. Multivariate analysis (MVA) of toxicity endpoints with SMI and baseline characteristics were analyzed by logistic regression analysis, and with overall survival (OS) using Cox regression analysis. Results: A total of 369 patients met inclusion criteria with median follow-up of 23.0mo (range 1-193mo), median age of 64y (range 29-88y), and were mostly male (51%). Most were clinical stage (AJCC 7th edition) IIIA (44%), IIIB (31%), or IV (10%), while 10% had upfront surgery and adjuvant chemotherapy. Most common regimen was cisplatin-based (48%). Median OS was 25.5mo and PFS was 14.0mo. Patients with low SMI were more likely to be younger (median age 70y vs 62y), ECOG performance status (PS) > 0 (74% vs 59%), lower BMI (median BMI 23.3 vs 27.7), and not receive cisplatin-based regimen (35% vs 53%). There was no difference in histology, stage, surgery, or every 3-week (q3w) chemotherapy dosing. On MVA, low SMI was associated with increased risk of G3+ heme toxicity (OR 1.74, p = 0.04) and increased hospital use (OR 1.79, p = 0.04). G3+ heme toxicity was also associated with surgery and q3w dosing, but not age, PS, BMI, or regimen. Hospital use was also associated with BMI, surgery, and cisplatin-based regimen, but not age, PS, or q3w dosing. G3+ heme toxicity (HR 1.48, p < 0.01), older age (HR 1.02, p = 0.02), and stage 4 (HR 3.32, p < 0.01) were associated with worse survival on MVA, but not low SMI (HR 1.25, p = 0.11), PS, BMI, surgery, or regimen. Conclusions: Low SMI predicted higher risk of G3+ toxicity during first cycle of chemotherapy. High-risk patients with low SMI experienced significant adverse events and should be considered for more aggressive symptom management or alternative treatment strategies.
Lung cancer risk in persons enrolled in low-dose CT screening (LDCT) versus incidental lung nodule programs (ILNP).
Authors: Liao Wei , Faris Nicholas , Fehnel Carrie , Goss Jordan , Pacheco Alicia , Pinsky Paul F , Smeltzer Matthew , Osarogiagbon Raymond U.
Published: June 2022

8553

Background: LDCT screening saves lives, but <10% of eligible persons participate; eligibility criteria are imperfect; geographic, racial and socio-economic disparities have emerged. ILNP may expand access to early detection. We compared rates of lung cancer diagnosis in LDCT and ILNP population subsets. Methods: Prospective observational cohort study of enrollees in LDCT and ILNP in a community healthcare system in AR, MS and TN. We compared LDCT vs 4 ILNP cohorts (C) based on USPSTF 2021 LDCT eligibility criteria: <50 years (C1, too young); >80 years (C2, too old); 50 – 80 years (C3, ineligible smoking history); 50 – 80 years (C4, eligible). For certain analyses, we stratified the LDCT cohort by baseline (T0) Lung-RADS score (0-2 v 3-4). We used a Cox model to calculate crude and adjusted hazard ratios (aHR) for lung cancer diagnosis within 24 months of enrollment. Results: From 2015-2021, 7050 persons were in LDCT- 6073 (86%) Lung-RADS 0-2 (no/benign lesions), 977 (14%) Lung-RADS 3 or 4 (possibly malignant lesion) on T0 scan; 17,579 were in ILNP, 16%, 10%, 57% and 16% respectively in C1-4. Demographics and tobacco use history of the ILNP cohorts differed strikingly; C4 was very similar to LDCT (Table). Black persons were significantly more in C1 (too young) and C3 (insufficient tobacco use). Diagnosis of lung cancer at 36 months ranged from 1% in C1 to 15% in C4, compared to 3% in LDCT; aHR for lung cancer diagnosis within 2 years ranged from 0.23 to 5.12 (all LDCT ref), but ranged from 0.04 to 1.02 with reference to LDCT Lung-RADS 3-4. Most patients in LDCT and ILNP C2-4 had early stage. There were proportionately more Black lung cancer patients in C1-4, and 3 times more Black patients in C3 and 4 than in LDCT. Conclusions: ILNP provides early-detection access to a larger, more diverse population than LDCT, potentially alleviating race and socio-economics-based outcomes disparities. [Table: see text]
Impact of trilaciclib on multilineage chemotherapy-induced myelosuppression events in patients with extensive-stage small cell lung cancer: Post-hoc analyses of data from randomized clinical trials.
Authors: Goldschmidt Jerome H. , Weiss Jared , Zhou Jenny , Wang Jessie , Young Joshua A. , Lemus Wirtz Esteban , Ruiz Julio , Huang Huan , Hart Lowell L.
Published: June 2022

8568

Background: Trilaciclib is a short-acting CDK4/6 inhibitor administered prior to chemotherapy for multilineage myeloprotection. Reduced occurrence of chemotherapy-induced myelosuppression (CIM) events across neutrophil, red blood cell, and platelet lineages was reported in 3 Phase 2 clinical trials of trilaciclib versus placebo in patients with extensive-stage small cell lung cancer (ES-SCLC). In this post-hoc trial analysis, we further assessed the impact of trilaciclib on the occurrence of single and concurrent multilineage CIM events. Methods: Analyses were conducted separately by line of chemotherapy. In the first-line (1L) setting, pooled data from the G1T28-05 and G1T28-02 trials, in which trilaciclib or placebo was administered prior to etoposide, carboplatin, and atezolizumab [E/P/A] and E/P, respectively, were used. In the 2/3L setting, analyses were based on data from the G1T28-03 trial where patients received trilaciclib or placebo prior to topotecan. The proportion of patients with single and concurrent multilineage CIM events and incidence rate were estimated per cycle and during the first 4 cycles of chemotherapy. Severe (grade ≥ 3 per CTCAE definition) CIM events of neutropenia (SN), anemia (SA), and thrombocytopenia (ST) were assessed. Concurrent CIM events were defined as having 2 or 3 lineage-specific CIM events overlap for ≥ 1 day. As sensitivity analyses, the occurrence of CIM events in patients with ES-SCLC receiving 1L treatment in the G1T28-05 and G1T28-02 studies was analyzed separately. Results: Compared with placebo, fewer patients receiving trilaciclib had single-lineage CIM events and concurrent events in 2 or 3 lineages during cycles 1–4 of 1L chemotherapy using pooled data from G1T28-05 and G1T28-02 (Table). A similar trend was observed in the 2/3L setting. Generally, SN occurred more frequently in earlier cycles, whereas SA and ST tended to occur later. The sensitivity analysis in each individual 1L trial yielded consistent results with the pooled analysis. Conclusions: Patients with ES-SCLC receiving trilaciclib prior to chemotherapy had fewer single and concurrent multilineage CIM events than patients receiving placebo. Clinical trial information: NCT03041311, NCT02499770, NCT02514447. [Table: see text]
Checkpoint inhibitor accessibility in 15,000+ Indian patients.
Authors: Ravikrishna Madala , Abraham George , Patil Vijay Maruti , Bhattacharjee Atanu , Noronha Vanita , Menon Nandini Sharrel , Joshi Amit , Prabhash Kumar
Published: June 2022

9012

Background: Access to newer therapies is an issue in low and low middle income countries. Hence we decided to audit our practice in the head and neck and thoracic medical oncology unit from 2015 to 2019 to study the accessibility of checkpoint inhibitors and factors influencing them. Methods: All patients who were registered in the head and neck and thoracic medical oncology unit between 2015-2019 were included in the study. The number of patients who received immunotherapy among them was identified from the prospective database of immunotherapy maintained in the department. We made a list of patients who were eligible for immunotherapy per year and identified how many of them received recommended immunotherapy. The indication for eligibility of immunotherapy was based on published pivotal data and its date of publication of the study online. For nominal and ordinal variable percentage with 95% CI was provided. Factors impacting the accessibility of immunotherapy were identified. Results: A total of 15,674 patients were identified who required immunotherapy; out of them only 444 (2.83%, 95% CI, 2.58-3.1) received it. The distribution of patients eligible as per cancer disease management group and time period is shown in the Table. Among head and neck cancer patients 4.5% (156 out of 3,435) received immunotherapy versus 2.35% (288 out of 12,239) among thoracic cancer patients (p < 0.0001). Among the general category (low socioeconomic), 0.29% (28 out of 9,405) versus 6.6% (416 out of 6,269) among the private category (high socioeconomic) received immunotherapy (p < 0.0001). While 3.7% (361 out of 9,737) among males versus 1.39% (83 out of 5,937) females received immunotherapy (p < 0.0001). There was also a temporal trend seen in the accessibility of immunotherapy (p < 0.0001, Table). Conclusions: The accessibility of immunotherapy is below 3% in India. Patients with head and neck cancers, those with private category and with male gender had higher access to this therapy. There was also a temporal trend observed suggesting increased accessibility over the years. [Table: see text]
Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC).
Authors: Goldman Jonathan W. , Horinouchi Hidehito , Cho Byoung Chul , Tomasini Pascale , Dunbar Martin , Hoffman David , Parikh Apurvasena , Blot Vincent , Camidge D. Ross
Published: June 2022

9013

Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for > 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (> 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]
Phase I trial of the RAF/MEK clamp VS-6766 in combination with everolimus using an intermittent schedule with expansion in NSCLC across multiple KRAS variants.
Authors: Minchom Anna Rachel , Sanchez Perez Vicky , Morton Cienne , Manickavasagar Thubeena , Nintos George , Lai-Kwon Julia Elizabeth , Guo Christina , Tunariu Nina , Parker Tom , Prout Toby , Parmar Mona , Turner Alison Joanne , Finneran Laura , Hall Emma , Pachter Jonathan A. , Denis Louis J. , Spicer James F. , Banerji Udai
Published: June 2022

9018

Background: VS-6766 is a small molecule RAF/MEK clamp that results in the reduction of p-MEK and p-ERK. Preclinical data show synergy of VS-6766 with the mTOR inhibitor everolimus across a panel of KRAS mutated (mt) NSCLC cell lines. This clinical trial evaluated the safety and efficacy of a novel intermittent regimen of VS-6766 and everolimus with an expansion in KRAS mt NSCLC (NCT02407509). Methods: The trial used a 3+3 dose escalation design with an intermittent once a week schedule A, and if tolerated, twice a week schedule B (Mon-Thu or Tue-Fri) for both drugs on a 3 weeks on/1 week off, 28 day cycle. Patients with RAS or RAF mt cancers were eligible for the dose escalation cohort, and 20 patients with KRAS mt NSCLC will be treated in the dose expansion cohort. Toxicity was evaluated by NCI CTC V4 and efficacy was evaluated using RECIST 1.1. Results: A total of 28 patients have been treated; median age 60 yrs (range 36-78), and median lines of previous treatment 3 (range 0-7). Sixteen patients have been treated in the dose escalation (3 in schedule A and 13 in the schedule B). The doses of 4 mg of VS-6766 and 5 mg everolimus (once weekly) were tolerated with no dose limiting toxicities (DLTs) and the dose intensity escalated to schedule B (twice weekly). At 4 mg VS-6766 twice weekly, DLTs were observed in two out of six patients and included grade 4 CPK elevation and grade 3 rash. Thus, the dose in schedule B (twice weekly) was de-escalated to 3.2 mg VS-6766 and the dose of everolimus was kept at 5 mg. No DLTs were reported in 6 patients and thus this was declared as the recommended phase 2 dose (RP2D). At the RP2D, the grade 3-4 drug related AE were rash (18%) and pruritus (7%). In the dose escalation cohorts, 3 partial responses (PRs) were reported (2 KRAS G12D low grade serous ovarian cancer and 1 NRAS Q61K mt thyroid cancer). In the KRAS mt NSCLC expansion cohort, 10 patients are evaluable for efficacy and 2 confirmed responses were reported ( KRAS mutations G12V and G13A) with an objective response rate (ORR) 20% to date. The disease control rate (PR + SD) at the first scheduled evaluation was 90%. The median progression free survival (PFS) in the KRAS mt NSCLC cohort is 6.35 months (95% CI 3.52 – not reached). Updated ORR and PFS data will be presented. Conclusions: A tolerable intermittent dosing schedule targeting both the MAPK and PI3K pathways has been established. The combination of VS-6766 with everolimus has shown activity in patients with a variety of KRAS mutation variants including responses in KRAS mt NSCLC.
A phase Ib/II study of AK112, a PD-1/VEGF bispecific antibody, as first- or second-line therapy for advanced non–small cell lung cancer (NSCLC).
Authors: Zhou Caicun , Ren Shengxiang , Luo Yongzhong , Wang Lei , Xiong Anwen , Su Chunxia , Zhang Zhihong , Li Wei , Zhou Jin , Yu Xinmin , Hu Yanping , Zhang Xiaodong , Dong Xiaorong , Hou Xiaoming , Dai Yuanrong , Song Weifeng , Li Baiyong , Wang Zhongmin Maxwell , Xia Yu
Published: June 2022

9040

Background: Besides the well-known antiangiogenic effects, anti-VEGF agents also modulate the tumor immune micro-environment, leading to synergic anti-tumor effects. AK112 is a humanized IgG1 bispecific antibody against PD-1 and VEGF. Here, we reported results of an ongoing phase Ib/II trial of AK112 in advanced NSCLC pts. Methods: Pts with stage IIIB/IIIC/IV NSCLC, ECOG PS 0-1 and negative oncogenic drivers were enrolled and given AK112 (10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W or 30 mg/kg Q3W) intravenously. The primary endpoints were ORR per RECIST v1.1 and safety. Results: At data cutoff (January 5, 2022), 94 pts were enrolled: median age 66.0 years (range: 48-75), PS 1 90.4%, male 85.1%, non-squamous 48.9%, PD-L1 positive (TPS ≥1%) 70.2% and treatment-naïve 84.0%. Of 83 pts evaluable for efficacy, ORR (unconfirmed, similarly hereinafter) and DCR were 22.2%/88.9%, 44.0%/92.0%, 37.9%/93.1% and 100%/100% at doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W and 30 mg/kg Q3W, respectively. When doses of AK112 > 10mg/kg Q3W, ORR and DCR were 42.9% (24/56) and 92.9% (52/56) in 56 evaluable pts, 56.3% (18/32) and 100% (32/32) in pts with TPS≥1% at 1st line setting, and 23.5% (4/17) and 76.5% (13/17) in pts with PD-L1 TPS < 1%, respectively. Grade≥3 treatment-related adverse events (TRAEs) occurred in 10.6% (10/94) pts, in which the most common event (occurring in > 1 pt) was pneumonia (2.1%, 2/94). No TRAEs led to permanent treatment discontinuation. Most frequent TRAEs (incidence ≥10%) were proteinuria (17.0%), hypertension (16.0%), lipase increase (12.8%), alanine aminotransferase increase (12.8%), blood urea increase (10.6%), apolipoprotein E increase (10.6%) and hyperglycaemia (10.6%). No significant difference in the incidences of TRAEs were observed between non-squamous and squamous pts. Conclusions: In advanced NSCLC, AK112 was well-tolerated and presented remarkable anti-tumor efficacy. Further phase III studies are planned to validate the findings of this study. Clinical trial information: NCT04900363.
Impact of STK11 copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer.
Authors: Gutierrez Catherine , Ricciuti Biagio , Alessi Joao Victor Machado , Pecci Federica , Barrichello Adriana Paula de Castro , Vaz Victor R. , Sholl Lynette M. , Awad Mark M.
Published: June 2022

9059

Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRASmut), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11mut), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11del). Given that 32.5% of STK11del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11del on ICI outcomes we excluded samples with STK11mut from this analysis. In all comers with NSCLC, STK11del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11del on clinical outcomes to PD-(L)1 blockade among KRASmut cases we found that STK11del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11del. No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRASwt NSCLCs, STK11del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11del. Among KRASmut but not KRASwt NSCLCs, cases with STK11del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.
Clinicopathologic and mutational landscape of BRAFV600E-mutant non–small cell lung carcinoma.
Authors: Sui Jane Sze Yin , Ladanyi Marc , Rudin Charles M. , Drilon Alexander E. , Riely Gregory J. , Kris Mark G. , Offin Michael
Published: June 2022

9084

Background: BRAF mutations (mts) occur in 2-5% of non-small cell lung cancers (NSCLC) with approximately 50% being BRAFV600E. Limited data is known regarding the mutational landscape (ML) and prognostic role of co-mutations in BRAFV600E NSCLC. We performed this study to evaluate clinicopathological characteristics and the impact of ML in BRAFV600E NSCLC. Methods: Patients (pts) with BRAFV600Emutant NSCLC were identified using MSK-IMPACT at Memorial Sloan Kettering Cancer Center between January 2014 to October 2021. Baseline clinicopathological characteristics and treatment outcomes were annotated. Due to the enrichment of SETD2 in BRAFV600E NSCLC, we conducted further analyses using cbioportal to identify co-mutations of SETD2 with other actionable mutations in NSCLC. Overall survival (OS) was assessed from the date of metastatic disease until death using the log-rank test. Results: BRAF mutations were detected in 5% of NSCLC samples (512/10220) with 22% (97/435 pts) being BRAFV600E. Of the 97 pts with BRAFV600E NSCLC identified: 57 pts (59%) were females, median age of 68 (range: 38-93 years), 58 pts (60%) were former smokers. All BRAFV600E tumors were adenocarcinoma and the median tumor mutational burden was 5 mt/Mb (range: 0-40). 46 pts (48%) with BRAFV600E NSCLC were diagnosed with de novo metastatic disease. Pts receiving targeted therapy at first, second, and subsequent lines of therapy numbered 17 (29%), 18 (31%), and 10 (17%) respectively. Co-alterations of BRAFV600E with TP53 and SETD2 were found in 45% (44/97) and 42% (41/97), respectively. There is a much lower prevalence of concurrent inactivating SETD2 mutations than with other actionable alterations in NSCLC: ROS1 (9%), ALK (8%), RET (8%), HER2 (6%), MET (5%), KRAS (5%), EGFR (2.9%) and BRAFnon-V600E (2%). Median OS in BRAFV600E+/ TP53+ vs BRAFV600E+/ SETD2+ were 35 vs 36 mos (HR 0.88m 95% CI 0.45-1.75, P= 0.71) and BRAFV600E+/ TP53+/ SETD2+ vs BRAFV600E+/ TP53-/ SETD2- were 19 vs 39 mos (HR 0.37, 95% CI 0.09-1.50, P= 0.06). Conclusions: Among the BRAFV600E lung adenocarcinomas, concurrent TP53 mutation and SETD2 inactivation define a patient subset with significantly shorter overall survival. Further studies are warranted to investigate the role of SETD2 mutations in the context of BRAFV600E in NSCLC pts.
Acquired EGFR-resistant mutations in non–small cell lung cancer (NSCLC).
Authors: Raez Luis E. , Baca Yasmine , Nieva Jorge J. , Mamdani Hirva , Lopes Gilberto , Borghaei Hossein , Socinski Mark A. , Nabhan Chadi , Wozniak Antoinette J. , Vanderwalde Ari M. , Uribe Carlos Carracedo , Khan Hina , Liu Stephen V. , Nagasaka Misako
Published: June 2022

9113

Background: EGFR mutations are present in more than 10% of patients (pts) with NSCLC in the US. While EGFR with tyrosine kinase inhibitors (TKIs) are effective, acquired resistance is expected. Known mechanisms include acquired EGFR mutations (e.g. 718V, c797x, 724s, 721s or T790M); copy number amplifications in MET, ERBB2, and PIK3CA; gene fusion events; and histological transformation. We herein present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Non-small cell lung cancer (NSCLC) tumor samples were submitted to Caris Life Sciences (Phoenix, AZ) for NextGen Sequencing (NextSeq, 592 Genes) and whole exome sequencing (NovaSeq, WES). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff >1). TMB was measured by totaling somatic mutations (TMB-high cut-off > 10 mutations per MB), genomic loss of heterozygosity (gLOH) was determined by WES. Patient treatment information was obtained from insurance claims data. Results: A total of 27,848 NSCLC tumors were evaluated and 3,223 (12%) had a EGFR sensitizing mutations. We found 60 tumors with common missense resistance mutations: 790 (n = 30, 0.9%), 797 (n = 38, 1.2 %), 718 (n = 11, 0.3%), 724 (n = 7, 0.2%) and 721 (n = 4, 0.1). Table 1 describes the frequencies, PD-L1 expression and the most common co-mutations. TMB-H (> = 10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. The most prevalent co-alterations were TP53 54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%) and other 15 co-mutations in less than 7% were seen. In the 30 T790M mutants, in addition to TP53 mutations, other prevalent co-mutations were PIK3CA (14%) and CTNNB1 (17%). In 797-mutant tumors, in addition to T790M, the most prevalent co-mutations were TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (8/11), exon 19 (3/11) or T790M mutations (3/11). G724 mutations were found in 7 patients (0.02%) and G721 mutations in 4 patients (0.01%). Conclusions: Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers. [Table: see text]
Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067.
Authors: Hodi F. Stephen , Chiarion -Sileni Vanna , Lewis Karl D. , Grob Jean-Jacques , Rutkowski Piotr , Lao Christopher D. , Cowey Charles Lance , Schadendorf Dirk , Wagstaff John , Dummer Reinhard , Queirolo Paola , Smylie Michael , Butler Marcus O. , Hill Andrew Graham , Marquez-Rodas Ivan , Haanen John B. A. G. , Durani Piyush , Wang Peter , Wolchok Jedd D. , Larkin James
Published: June 2022

9522

Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI); median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9–NR), 24.7 mo (16.0–38.7), and 8.0 mo (6.5–8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up; updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI; 3 NIVO; 2 IPI), none were treatment-related; 4 were due to melanoma progression; 1 was due to an unknown cause; and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses. Clinical trial information: NCT04540705. [Table: see text]
Autoantibodies as potential biomarkers of immune-related adverse events in patients with advanced cutaneous melanoma treated with immune checkpoint inhibitors.
Authors: Gandhi Aesha , Taylor John , Morici Michael , Reid Anna , Meniawy Tarek , Khattak Muhammad Adnan , Gray Elin , Millward Michael , Zaenker Pauline
Published: June 2022

9536

Background: The majority of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAE). It is currently not possible to predict the development of irAEs using biomarkers. Here we evaluated the IgG autoantibodies (AAbs) profile in pre-treatment sera of cutaneous metastatic melanoma patients treated with ICIs to identify AAbs that are associated with irAEs. Methods: Clinical data of patients with metastatic melanoma treated with pembrolizumab or nivolumab monotherapy (n = 48) or combination ipilimumab and nivolumab (n = 37) was retrospectively evaluated. irAEs were graded using CTCAE v5.0. Sera from the 85 patients were evaluated for IgG AAbs using the HuProt™ microarray v4.0 covering 23,059 proteins ( > 81% of the human proteome). AAb profiles were compared between groups (any irAEs vs no irAEs), using the no irAEs group as control group. Results were inputted into the Advaita Bio’s iPathwayGuide software to find significantly differentially expressed AAbs using p < 0.05 and Log2FC > 0.6, and identify relevant biological pathways. Results: Out of 85 patients, 60 experienced any grade irAEs, 29 of 48 (60.4%) in the PD-1 group and 31 of 37 (83.8%) in the combination group. We found 758 proteins were differentially elevated, 102 in the in the PD-1 group and 666 in the combination treatment group. A comparison of these groups identified 10 AAbs that were elevated in patients experiencing irAEs independent of ICI regimen. These targeted proteins are highly expressed in tissues that are commonly affected by irAEs. Previous studies have shown their links to autoimmune and inflammatory conditions such as dermatitis and thyroiditis. Pathway analysis shows the RIG like receptor signalling pathway, which has been associated with autoinflammatory conditions, was significantly affected in the PD-1 group (p = 0.011), but not in the combination group (p = 0.442). Other pathways involved included the NOD-like receptor, purine and D-amino acid metabolism which play a role in innate immune system and assembly of inflammasomes and maturation, pro-inflammatory cytokines and mediators that contribute to inflammatory response. Conclusions: Further analyses are being conducted to identify the correlation of irAE type and severity to specific autoantibodies which will be presented. Prospective studies are required for validation of these AAbs specificities. This approach could be used to identify patients at high risk of irAEs, for treatment monitoring to maintain an effective stimulation of the patient’s anti-cancer immune response, to determine if treatment cessation is required and prevent hospitalisation or lengthy immunosuppression to treat irAEs.
Prognostic significance of the CP-GEP assay combining clinicopathologic factors and gene expression profiling in patients (pts) with AJCC v8 stage I/II cutaneous melanoma (CM).
Authors: Amaral Teresa Maria Santos , Sinnberg Tobias , Chatziioannou Eftychia , Niessner Heike , Leiter Ulrike M. , Keim Ulrike , Forschner Andrea , Dwarkasing Jvalini , Meerstein-Kessel Lisette , Rademaker Thomas , Wever Renske , Eggermont Alexander M. , Flatz Lukas , Forchhammer Stephan
Published: June 2022

9564

Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p<0.001), the 5-y DMFS rate was 86% and 96% (HR 4.35; p<0.001) and the 5-y OS was 85% and 95% (HR 3.2; p=0.001), respectively for high and low-risk CP-GEP score. In multivariate Cox regression analysis for RFS including Breslow thickness, ulceration and age, contribution of CP-GEP score remained independently significant (HR 2.75; p=0.0008) compared to age (HR 1.03; p<0.0007), Breslow (HR 1.21; p<0.0001) and ulceration (HR 1.37; p=0.1694). Conclusions: CP-GEP risk score is a non-invasive and independent prognostic model for risk of relapse in stage I/II melanoma validated in this study. It identifies SLN negative pts at high risk of relapse and should be considered for complementing AJCC classification and for inclusion in future clinical trials.[Table: see text]
The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases: A multicenter cohort study.
Authors: Olofsson Bagge Roger , Holmberg Carl Jacob , Hieken Tina J. , Zager Jonathan S. , Long Georgina V. , Van Akkooi Alexander Christopher Jonathan , Karakousis Giorgos C , Pallan Lalit , Vetto John T. , Gyorki David E. , Ascierto Paolo Antonio , Dummer Reinhard , Hui Jane Yuet Ching , Schachter Jacob , Helgadottir Hildur , Kroon Hidde , Rothermel Luke Daniel , Carlino Matteo S. , Broman Kristy Kummerow , Ny Lars ,   The ITforIT Research Collaboration
Published: June 2022

9569

Background: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The aim of this study was to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international high‐volume melanoma centers. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c and N3c) and without distant disease (M0). Patients were treated with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). We assessed response rates, progression-free survival (PFS), melanoma-specific survival (MSS) and overall survival (OS). Results: A total of 287 patients from 21 institutions in 8 countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. Monotherapy with a PD-1 or CTLA-4 inhibitor was given in 233 (81%) and 23 (8%) patients respectively, while 31 (11%) received both in combination. Overall response rate was 56%, complete response (CR) rate 36% and progressive disease (PD) rate 32%. Median PFS was 10 months (95% CI 7.4-12.6 months) with a 1-, 2- and 5-year PFS rate of 48%, 33% and 18% respectively. Median MSS was not reached, and the 1-, 2- and 5-year MSS rates were 95%, 83% and 71% respectively. Conclusions: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the optimal role for systemic immunotherapy in the context of multimodality therapy including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
Use of Merlin Assay to identify patients with a low-risk for SN metastasis in a prospective multicenter Dutch study of a primary melanoma gene-signature (CP-GEP model) to predict sentinel node status during COVID-19.
Authors: Stassen Robert , Mulder Evalyn , Veringa Antoine , Mooyaart Antien , Dwarkasing Jvalini , Tempel Dennie , van der Hage Jos A. , Lendfers Sandra , Aarts Maureen J.B. , Verhoef Cornelis , Francken Anne Brecht , Grunhagen Dirk J.
Published: June 2022

9571

Background: Approximately 70%-85% of patients who undergo sentinel lymph node biopsy (SLNb) show no nodal metastasis in the sentinel node (SN). The clinicopathological and gene expression profile (CP-GEP) model ( Merlin Assay) was developed and validated to identify patients that may forgo the SLNb surgery due to their low risk for for nodal metastasis This study was initiated during the first wave of Covid-19 pandemic to allow for surgical triage on SLNb and evaluate the implementation of the Merlin assay in clinical practice. Methods: This study was conducted in four designated melanoma centers in the Netherlands. Patients (age > 18y) with newly diagnosed melanoma of the skin, eligible to undergo SLNb were screened for study inclusion. Main exclusion criteria was prior history of primary melanoma ( > T1b) in the past 5 years. After enrollment, tissue sections of the primary melanoma were centrally reviewed at the Erasmus MC Cancer Institute to determine Breslow thickness at primary diagnosis. FFPE tumor tissue was dispatched for molecular analysis of eight target genes known to play a role in cancer development. In combination with age, Breslow thickness, and GEP outcome, risk of having nodal metastasis was calculated. Results were binary presented as 'CP-GEP low risk' and 'CP-GEP high risk'. SLNb status was used as gold standard for comparison. Results: A total of 177 patients were analyzed using the CP-GEP model. Median age was 64 years (IQR 52-73) Median Breslow thickness was 1.4mm (IQR 1.0-2.4). Of all patients 28.2% was diagnosed with T1, 40.7% with T2 and 20.9% with T3 melanoma. Corresponding positivity rate was 7%, 14% and 29% respectively. A total of 24 out of 177 patients had a positive SLNb. Median turn-around time from inclusion to CP-GEP result was 15 days. Overall 37.1.% of patients had a CP-GEP low risk profile. The CP-GEP model had a NPV of 94.6%. Conclusions: This is the first prospective multicenter implementation study for the Merlin assay. Results are in line with previous validation studies. The CP-GEP model could accurately identify patients at low risk for SN metastasis. Implementation in clinical practice is feasible based on current turn-around time. In the future, using the Merlin assay to deselect patients for SLNB may allow for a reduction of surgery in patients with melanoma.
A single-center experience of 98 patients (pts) with regionally metastatic Merkel cell carcinoma (MCC) of known (MCCKP) and unknown (MCCUP) primary at presentation.
Authors: Cope Brandon , Witt Russell G. , Chiang Yi-Ju , Seervai Riyad Navroz , Fisher Sarah B. , Lucci Anthony , Wargo Jennifer Ann , Lee Jeffrey Edwin , Farooqi Ahsan Saleem , Bishop Andrew , Gershenwald Jeffrey E. , Goepfert Ryan , Wong Michael K.K. , Guadagnolo Beverly Ashleigh , Ross Merrick I. , Aung Phyu P , Mitra Deverati , Keung Emily Zhi-Yun
Published: June 2022

9576

Background: MCC is a rare skin cancer historically associated with poor survival rates and which is increasing in incidence. A small number of retrospective series suggest that MCCUP may be associated with better prognosis than MCCKP while others report worse outcomes. Recent advances in immunotherapy have changed the multimodal treatment landscape and outcomes of advanced MCC pts. We describe our experience with the management and outcomes of pts presenting with regional MCC metastasis of known and unknown primary origin. Methods: A retrospective review of pts with clinical regional disease at MCC diagnosis treated at our institution from 3/2003-3/2021 was performed. Clinicopathologic variables and outcomes were assessed. Overall survival (OS), recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by the Kaplan Meier method. Results: Of 98 pts with regional disease on exam at presentation, 56 (57%) had MCCUP and 42 (43%) had MCCKP. Median follow-up from diagnosis to last follow-up or death was 33 months. Pts were generally older (MCCUP vs MCCKP: 68.7 vs 73.1 years), male (MCCUP vs MCCKP: 82% vs 74%) and Caucasian (MCCUP vs MCCKP: 84% vs 83%). Over half the pts had a history of another malignancy (MCCUP vs MCCKP: 52% vs 60%) with 9% and 14% being immunocompromised at diagnosis, respectively. After completion of staging workup, MCCUP pts had earlier stage disease at presentation compared with MCCKP pts (stage IIIA: 80% vs 55%, IIIB: 5% vs 31%, IV: 15% vs 14%, respectively). The cervical nodal basin was most commonly involved in MCCUP pts while regional disease was more varied in MCCKP pts (MCCUP vs MCCKP: cervical 54% vs 28%, axillary 15% vs 33%, inguinal 33% vs 3%, inguinal and pelvic 0% vs 11%, in transit 0% vs 14%). Formal lymphadenectomy (LND) was performed in 27 (48%) and 18 (43%) of MCCUP and MCCKP pts, respectively. Of these pts, 33% and 50% received neoadjuvant systemic therapy, most commonly immunotherapy; 70% and 55% received adjuvant radiotherapy. MCCUP pts had better outcomes compared to MCCKP pts (Table), with longer RFS in pts who underwent LND (not reached [NR] vs 13.1 months) as well as longer PFS in pts who did not undergo LND (17 vs 9 months) with longer OS in both subgroups (LND: NR vs 102.7 months; no LND: 74.4 vs 48.7 months). Conclusions: MCCUP patients with regional disease on exam at presentation have improved survival compared to MCCKP. Current stage III survival estimates may underestimate survival in patients with resectable disease. [Table: see text]