bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of polymeric micelle paclitaxel (pm-Pac) plus tislelizumab and carboplatin for first-line treatment of patients with advanced squamous non-small-cell lung cancer.
Authors: Shi Meiqi , Zhao Yufang , Wang Li , Peng Wei , Zhu Xiangzhi , Li Xingwang , Wang Lv-hui , Ma An-mei , Tang Yi-qun
Published: June 2023

9036

Background: The pm-paclitaxel formulation for injection (pm-Pac), a novel drug delivery system composed of nanoparticle-encapsulated paclitaxel micelles, combined with cisplatin has been proven to improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). But the efficacy and safety of pm-Pac in addition to PD-1/PD-L1 inhibitors had never been reported before. Methods: Treatment-naive, stage IIIB/IV Sq-NSCLC patients with ECOG PS 0-2(≤1, 91.1%) were eligible. Participants were given intravenous Tislelizumab (200mg, d1) plus pm-Pac (230 mg/m2, d1) and carboplatin (AUC 5, d1), every 3 weeks until progression or unacceptable toxicity, with local radiotherapy or surgery allowed if treatment needed. The primary endpoints were ORR and safety. The secondary endpoints include DCR, PFS, and OS. AEs were graded according to CTCAE v5.0. Results: From Nov 2021 to Dec 2022, 45 patients were enrolled. The median age was 68 years (range 41-84), and most were male (93%) and former/current smokers (87%). 3 patients had baseline brain metastases and 31 patients had baseline PD-L1 evaluated. Twenty-two patients (48.9%) received subsequent local treatment because of the stable efficacy, including 18 radiotherapy and 4 surgery. Among all, 2 achieved confirmed CR, 36 achieved PR, 7 achieved SD, ORR was 84.4% and DCR was 100%. PFS and OS were immature. Kaplan-Meier survival analysis indicated that the 6m-PFS rate was 94.8% (95%CI:89.8%，97.6%), and a total of 41 (91.1%) patients are still alive on 1L treatment at the last follow-up on Feb 2023.The most common TRAE were alopecia (91.1%), leukopenia (80%), peripheral neurosensory numbness (55.6%) and extremity pain (24.4%). The most common grade 3 or higher AE was neutropenia (33.3%), which is commonly associated with chemotherapy. Conclusions: This is the first report about the new chemo-drug pm-Pac plus PD-1 inhibitor regimen that significantly improved ORR for advanced Sq-NSCLC with a tolerable safety profile, supporting further development of this new combination in the first-line treatment. Response rates. [Table: see text]
Prognostic and predictive implications of plasma ctDNA in guiding first-line targeted therapy for metastatic HER2-mutant non-small cell lung cancer (NSCLC).
Authors: Liu Si-Yang , Jee Justin , Santini Fernando Costa , Schoenfeld Adam Jacob , Eichholz Jordan , Johnson Kaylie , Martinez Andres , Guo Jiannan , Riaz Nadeem , Lee Nancy Y. , Pike Luke Roy George , Scher Howard I. , Drilon Alexander E. , Arcila Maria E. , Reis-Filho Jorge S. , Razavi Pedram , Jones David Randolph , Rudin Charles M. , Isbell James M. , Li Bob T.
Published: June 2023

9052

Background: Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted drug approved for NSCLC with human epidermal growth factor receptor 2 ( HER2, ERBB2) mutation in the second or later line settings. However, the optimal first-line treatment for these patients remains unclear. Access to rapid tissue sequencing is not always available, thus presenting challenges to first-line drug development. Circulating tumor DNA (ctDNA) analysis has the potential to overcome these obstacles to guide optimal first-line targeted therapy for patients with HER2-mutant NSCLC. Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx Lung. Results: We identified 64 patients with metastatic HER2-mutant NSCLC who had received at least one line of systematic therapy. The median age was 63 years (range: 23–90), and there were more women (n = 38, 60%), and never-smokers (n = 38, 60%). The activating HER2 mutations included exon 20 insertions (73%), exon 8 (11%), 19 (11%), and 20 SNVs (5%). Plasma ctDNA was tested before initial therapy in 40 patients with a median overall survival (OS) of 28 months (95% CI 21-34), in whom 31 patients (78%) had at least one detectable ctDNA alteration by MSK-ACCESS and ctDx Lung. 55% (17/31) received chemoimmunotherapy with pembrolizumab as the first-line treatment. The median time to treatment discontinuation (TTD) was 6 months (95%CI 5.5-6.9). Additionally, 19% of patients (6/31) received a HER2-targeted antibody-drug conjugates (ADC) as first-line treatment with a median TTD of 6 months (95% CI 2-10), including 5 with T-DM1 and one who received first-line T-DXd treatment with a TTD of 9 months. Patients with baseline ctDNA alterations had significantly shorter OS (hazard ratio (HR), 5.25; 95% CI, 1–24; p = 0.019). Conclusions: Baseline plasma ctDNA has the potential to guide first-line targeted therapy for patients with HER2-mutant NSCLC. As an independent negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies to avoid underestimating the effects of therapy.
Treatment patterns and unmet need for patients with advanced non-small cell lung cancer and poor performance status: A real-world evidence study.
Authors: Liu Stephen V. , Sussell Jesse , Boudreau Denise , Schuldt Robert , Harton Joanna , Bara Ilze , Pregenzer An , Porter Jason
Published: June 2023

9077

Background: Performance Status (PS) is prognostic for poorer survival in oncology. Poor PS (pPS) may lead to inferior outcomes both as an independent factor and by limiting the range of available treatment options and the ability of patients to tolerate those regimens. Despite high real-world prevalence, patients with pPS are consistently underrepresented in clinical trials. Limited information is available regarding current treatment patterns for patients with pPS and advanced or metastatic non-small cell lung cancer (mNSCLC). Methods: We conducted a retrospective analysis using the nationwide de-identified Flatiron Health electronic health record (EHR)-derived database, selecting patients with mNSCLC diagnosed between 2017-2022 without EGFR or ALK genomic tumor aberrations. We estimated the prevalence of pPS (ECOG 2-3) within this cohort, and described common systemic treatment patterns by year and by PD-L1 status. For the subset of patients treated with pemetrexed/pembrolizumab/carboplatin (PPC), we estimated the association between pPS versus good PS (gPS - 0/1) and early discontinuation ( < 4 cycles) or dose reduction (AUC < 4) of carboplatin using logistic regression controlling for observable confounders. Results: One quarter (24%) of the 22,575 patients in our sample had pPS. Relative to patients with gPS, patients with pPS were more likely to be older (mean age 72 vs. 69y, p < 0.001), to have stage IV cancer (62% vs 56%, p < 0.001) and less likely to have known PD-L1 status (60% vs. 63%, p = 0.002). The fraction of patients with no documented treatment was substantially higher among pPS versus gPS (37% vs. 21%). In the subset of patients with PS3, 53% of patients had no documented treatment. The most common treatment regimens among pPS patients were mono-immunotherapy (mono-IO - 19%) and PPC (15%). Use of mono-IO was positively correlated with higher PD-L1 expression (44% vs. 14% vs. 5.9% in PD-L1 high/low/negative, respectively). No documented treatment was negatively correlated with PD-L1 status (26% vs. 35% vs. 42%). Among patients with PS3, higher rates of no documented treatment were observed (39% vs. 50% vs 58% for PD-L1 high/low/negative, respectively). Anti-CTLA-4 combination use was low regardless of PS. pPS was associated with greater likelihood of early carboplatin discontinuation, (adjusted odds ratio, aOR 2.06), and dose reduction (aOR 1.75), both p < 0.001. Conclusions: One quarter of patients with mNSCLC have pPS. These patients are almost twice as likely to receive no treatment as those with gPS, and within the subset treated with the most common platinum containing regimen (PPC), pPS patients are also more likely to both initiate carboplatin at a reduced dose, and to discontinue it prior to completion. This suggests a substantial unmet need for this important subset of patients with mNSCLC.
Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.
Authors: Paz-Ares Luis G. , Paulus Astrid , Zemaitis Marius , Cicenas Saulius , Zvirbule Zanete , Felip Enriqueta , Sanfridson Annika , Rydberg-Millrud Camilla , Magnusson Susanne , Losic Nedjad , Garcia-Ribas Ignacio
Published: June 2023

9089

Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1st or 2nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2nd line post pembrolizumab) showed complete responses, one observed after >40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]
RET testing and treatment patterns among patients with aNSCLC in US clinical practice.
Authors: Kim Eunice , Sussell Jesse , Ng Carmen , Nedzesky Justin , Zhang Qing , Ngiam Celina , Mansfield Aaron Scott
Published: June 2023

9091

Background: Biomarker testing, including for rearrangement during transfection (RET), is recommended and important in selecting efficacious targeted therapy for patients with advanced non-small cell lung cancer (aNSCLC). This retrospective cohort study characterized RET testing and treatment patterns among aNSCLC patients in clinical practice. Methods: We used the nationwide Flatiron Health electronic health record-derived de-identified database to select patients diagnosed with aNSCLC (stage ≥IIIB) from 2017-2022. We measured rates of RET testing (test result ≤90 days after advanced diagnosis). We used logistic regression to identify baseline characteristics predictive of timely testing. Finally, we described treatment patterns for patients with RET+ aNSCLC before and after the US approval of RET inhibitors. Results: Among 26,329 aNSCLC patients, rates of RET testing ≤90 days after advanced diagnosis increased from 25% (2017 Q1) to 73% (2022 Q1). Patients were less likely to receive RET testing within 90 days if they were Black (multivariate odds ratio [OR] 0.8) or Hispanic (OR 0.8) compared to White, or had Medicare (OR 0.9; all p<0.001) compared to commercial insurance. Patients were more likely to receive RET testing within 90 days if they were in the highest socioeconomic quintile (OR 1.4), had de novo disease (OR 2.1), or no history of smoking (OR 1.3; all p<0.001). Between 2017 and 2022, there were increases in the use of next-generation sequencing (66% to 89%) and blood samples for biomarker testing (25% to 49%) and a decrease in mean days from diagnosis to test result (33 to 28) for the first RET test among those who had testing within 90 days. Among all patients with aNSCLC tested within 90 days (n=12,275), 73 were RET+ and received 1L treatment ≤90 days after advanced diagnosis. The most common 1L treatments before (n=35) and after (n=38) RET inhibitor approval were chemotherapy (40%) and RET inhibitor (42%), respectively (Table). Conclusions: RET testing has increased over time, but certain patient subgroups are less likely to receive timely RET testing and therefore may not be optimally treated. Among patients with RET+ aNSCLC identified after RET inhibitor approval, only 42% were treated with a RET inhibitor in the 1L setting. These results suggest both disparities in access to RET testing and unmet medical need among patients with RET+ aNSCLC. [Table: see text]
Explore ALK: Alectinib activity in patients with ALK+ metastatic non-small cell lung cancer—A national real world analysis (GFPC 03-2019).
Authors: Swalduz Aurélie , Rousseau-Bussac Gaelle , Guisier Florian , Doubre Helene , Fournel Pierre , Falchero Lionel , Bigay Game Laurence , Veillon Remi , Marcq Marie , Ricordel Charles , Decroisette Chantal , Dano Domitille , Justeau Gregoire , Martinez Stéphanie , Cortot Alexis B , Morel Hugues , Greillier Laurent , Descourt Renaud
Published: June 2023

9092

Background: Alectinib is a standard of care option in advanced ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients (pts), with efficacy established by phase 3 trials, in first-line and beyond. There are few efficacy data in unselected populations. Methods: The objective of this study was to evaluate the efficacy of alectinib in real-world setting. All ALK+ advanced NSCLC pts initiating alectinib, between December 13, 2017 (date of access in France) and June 27, 2020, whatever the line, were included in explore ALK study. Patient characteristics, alectinib duration of treatment (DOT), progression-free survival assessed locally (rwPFS), overall survival (OS) according to the prescription line of alectinib, the presence of brain metastases at alectinib initiation, response rate and tolerance were collected from the medical files. Results: The analysis included 223 pts: 46.2% were men, 84.7% had no smoking history or were former smokers, median age was 59 (22-101) years and 95% were adenocarcinomas. Alectinib was initiated as first-line treatment in 119 pts, with a PS of 0/1/>1 in 42%/31%/27% of cases, a median number of metastatic sites of 2 (cerebral, hepatic, bone in 33%, 24% and 32% of cases). In first-line setting, after a median follow-up of 33.7 months (95%CI, 32.2-37.5), the median of rwPFS and DOT were 28.1 (95%CI, 20.7-40.4) and 26.9 (95%CI, 20.2-31.3) months, respectively. The median OS was not reach (NR), the 3-year OS rate was 72.1%. The rwPFS was not significantly different depending on whether or not the patient has brain metastases, 28.1 (95% CI, 14.5-NR) and 30.5 (85% CI, 18.9-40.4) months, respectively. The best response was complete (CR), partial (PR) and stable (SD) in 21%, 58% and 17%. The cerebral response, evaluable in 30/39 of the pts, was CR, PR and SD in 26%, 46% and 23% respectively; 33% of pts had a grade 3 adverse event, resulting in a temporary interruption of treatment in 7.6% of cases and a permanent discontinuation in 5.9% of cases. At the time of progression, 48.1% of pts had a new biopsy (66% of tissue biopsy). Efficacy data for alectinib prescribed as second line and above are summarized in the table. Conclusions: In this large real-world, cohort of unselected advanced ALK+ NSCLC pts, alectinib initiated in 1st-line or beyond provides similar efficacy and safety results as obtained in phase III clinical trials. [Table: see text]
Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.
Authors: Liu Liang , Zhou Li , Ren Xiubao , Zhang Weihong , Xiong Yanjuan ,   CCICC
Published: June 2023

9096

Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .
Safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with non-small cell lung cancer (NSCLC): An open-label, phase Ib trial.
Authors: Fang Wenfeng , Zhao Yuanyuan , Huang Yan , Zhang Yaxiong , Hong Shaodong , Huang Yihua , Zhao Hongyun , Yang Yunpeng , Zhao Shen , Chen Gang , Zhou Huaqiang , Ma Yuxiang , Zhou Ningning , Zhang Li
Published: June 2023

9105

Background: Currently, limited targeted therapies are available for HER2 mutant NSCLC patients. Previous studies have shown the antitumor activity of pyrotinib in advanced NSCLC patients with HER2 mutations. Inetetamab is a recombinant humanized anti-HER2 monoclonal antibody. Whether inetetamab combined with pyrotinib could show manageable safety and more active antitumor activity remains unknown. This study was designed to evaluate the safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with advanced NSCLC. Methods: This study was an open-label, phase Ib study. The HER2 mutant patients with locally advanced or metastatic NSCLC were assigned to receive inetetamab combined with pyrotinib. The study consisted of dose-escalation part and dose-expansion part. During dose-escalation period, the parallel "3+3" dose-escalation design was used to determine the dose-limiting toxicity (DLT). Inetetamab was administered every 3 weeks (8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles) with pyrotinib (dose-escalation part, 240mg QD, 320mg QD; dose-expansion part, 320mg QD). Primary endpoint of the study was DLT dosage and safety. The DLT was assessed during the 21-day DLT evaluation period after the first dose. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression free survival and overall survival. Results: Between August 6, 2021, and August 25, 2022, 48 patients were enrolled. No DLT occurred during pyrotinib 240mg and 320mg escalation period. Therefore, pyrotinib 320mg was chosen as expansion dose. The most common treatment-related adverse events (TRAEs) were diarrhea (66.7% [2/3] in pyrotinib 240mg group, 95.6% [43/45] in pyrotinib 320mg group), rash (66.7% [2/3] in pyrotinib 240mg group, 22.2% [10/45] in pyrotinib 320mg group) and vomiting (0 in pyrotinib 240mg group, 24.4% [11/45] in pyrotinib 320mg group). TRAEs were generally Grade (G) 1-2. Only 7 patients reported G3 TRAE (1 in pyrotinib 240mg group, 6 in pyrotinib 320mg group). The preliminary efficacy was shown in the table below. The ORR and DCR of group receiving inetetamab with pyrotinib 240mg were 0% and 66.7%, respectively. The ORR and DCR of inetetamab with pyrotinib 320mg group were 36.6% and 85.4% respectively. The relationship between different mutation subtypes or co-mutations and efficacy will be updated during the conference reports. Conclusions: The preliminary data of inetetamab in combination with pyrotinib showed manageable safety and compelling antitumor activity in advanced NSCLC patients harboring HER2 mutations. Clinical trial information: NCT05016544 . [Table: see text]
Amivantamab and lazertinib in treatment-naïve EGFR-mutated advanced non–small-cell lung cancer (NSCLC): Long-term follow-up and ctDNA results from CHRYSALIS.
Authors: Lee Se-Hoon , Cho Byoung Chul , Han Ji-Youn , Cho Eun Kyung , Lee Jong-Seok , Lee Ki Hyeong , Curtin Joshua C , Gao Grace , Xie John , Schnepp Robert W. , Bauml Joshua Michael , Knoblauch Roland E. , Thayu Meena , Kim Dong-Wan
Published: June 2023

9134

Background: CHRYSALIS (NCT02609776) evaluated the combination of amivantamab (ami) and lazertinib (laz) in treatment-naïve patients (pts) with epidermal growth factor receptor ( EGFR)-mutated NSCLC. As previously reported, all 20 pts achieved a partial response (overall response rate of 100%) but interpretation of long-term outcomes was limited by the length of follow up (Cho Ann Oncol 2020;31:suppl_4, 1258O; Cho J Thorac Oncol 2022;17:S126, P1.16-01). Herein, we present long-term results from this treatment-naïve cohort. Methods: The treatment-naive cohort enrolled pts with EGFR exon 19 deletion (ex19del) or L858R mutated advanced NSCLC. All pts received 1050 mg IV ami (1400 mg if ≥80 kg) and 240 mg oral laz. Response was assessed by the investigator per RECIST v1.1. Circulating tumor DNA (ctDNA) was analyzed from plasma samples prior to initiation of treatment, at Cycle 3 Day 1, and at end of treatment (EOT). Results: Of the 20 pts enrolled in the treatment-naive cohort (median 62.5 years, 55% women, all Asian), 11 had EGFR ex19del and 9 had L858R NSCLC. As of Nov 15, 2022, the median follow-up and duration of treatment were 33.6 and 33.5 months, respectively. Ten (50%) pts were progression-free and remained on treatment, including 7 of 11 (64%) with ex19del and 3 of 9 (33%) with L858R. The median duration of response (DOR), median progression-free survival (PFS), and median overall survival (OS) were not estimable. The estimated landmark PFS rate was 85% at 12 months, 65% at 24 months, and 51% at 36 months. Of note, 2 (10%) pts were treated beyond progression. The longest ongoing pt has a duration of treatment of 37.2 months and DOR of 35.7 months. Treatment-related dose interruptions, reductions, and discontinuations of either ami and laz occurred in 7 (35%) pts, 8 (40%) pts, and 1 (5%) pt, respectively. The safety profile was consistent with prior reports, with predominantly on-target EGFR- or MET-related adverse events. Among the 10 pts who discontinued treatment, 4 submitted samples for ctDNA analysis at both baseline and EOT. There was 1 pt with new PIK3CA mutations, 1 with low-level HER2 amplification, 1 pt with a new CCNE1 and EGFR amplification, and 1 pt with no new mutations detected. Updated data on ctDNA at EOT may be available at the time of congress presentation. Conclusions: At a median duration of treatment of 33.5 months, median DOR, PFS, and OS have not been reached in treatment-naïve pts receiving ami+laz, with 50% remaining progression-free and on treatment. No new safety signals were identified. The ongoing phase 3 MARIPOSA study (NCT04487080) is further investigating ami+laz vs osimertinib vs laz in previously untreated, EGFR-mutated, advanced NSCLC. Clinical trial information: NCT02609776 .
Role of nivolumab maintenance therapy in advanced melanoma patients following severe immune-related adverse events from combination nivolumab and ipilimumab.
Authors: Maloney Anna , Giobbie-Hurder Anita , Fogarasi Miklos C. , Ott Patrick Alexander , Hodi F. Stephen , Sussman Tamara A. , Silk Ann W. , Haq Rizwan , Liu David , Insco Megan Leigh , Buchbinder Elizabeth Iannotti
Published: June 2023

9520

Background: The combination of ipilimumab (ipi), and nivolumab (nivo) has been shown to be a highly effective treatment for metastatic melanoma. However, immune-related adverse events (irAEs) are common with this treatment, leading to treatment interruption and the use of immunosuppressive agents. There are no data on the impact of resuming single agent nivo on survival outcomes following recovery from the irAE and completion of immunosuppressive treatment. Some physicians hold therapy permanently as done on clinical trials and other physicians resume nivo after steroid taper. Methods: In this retrospective analysis, we examined a cohort of patients treated with ipi/nivo who developed irAEs that required treatment interruption and immunosuppressive therapy. The differences in practice patterns among physicians at our institution allowed us to examine the effect of single agent nivo resumption on survival after treatment of irAEs. Multivariate analysis of clinical factors associated with improved survival was performed. Results: We identified 165 patients who were treated with ipi/nivo and developed irAEs requiring treatment interruption and immunosuppressive therapy. To remove any impact of immediate disease progression on the analysis patients who progressed on ipi/nivo prior to or during treatment hold were removed from analysis. Of the remaining 131 patients, 45 resumed single agent maintenance nivo following the resolution of toxicity and completion of steroid taper. When stratified by age and adjusted for sex, M-stage, LDH, duration of therapy, and type of irAE causing the treatment pause, the effect of resumption of nivo upon survival remained highly significant (p = 0.001). Patients who resumed nivo had an 82% reduction in the hazard of death compared with patients who had not yet or never resumed nivo (HR: 0.18, 95% CI: 0.06 to 0.52). Of the patients who resumed nivo, 12 (26%) patients had subsequent irAEs with 5 patients having grade 3 irAEs (only one of whom had a recurrence of the prior ipi/nivo associated toxicity) and no grade 4 or 5 irAEs were noted. Conclusions: The resumption of single agent maintenance nivolumab following a treatment hold for ipi/nivo associated irAE and completion of immunosuppressive therapy increased overall survival compared to discontinuing nivo permanently in patients with metastatic melanoma after stratification for many factors. Toxicity observed post resumption of single agent nivolumab was manageable with no severe irAEs observed. These results suggest that restarting maintenance nivo post irAEs should be studied prospectively.
Real-world treatment patterns and clinical outcomes among subgroups of BRAF-positive metastatic melanoma patients treated with dabrafenib + trametinib.
Authors: Eroglu Zeynep , Tang Jackson , Byrne Clare , Connolly Lucy , Shah Rohan , Truong Thach-Giao
Published: June 2023

9521

Background: Whether disease attributes such as tumor burden or central nervous system (CNS) metastases can affect outcomes for patients with BRAF+ metastatic melanoma (MM) is currently unclear. This study examined real-world patient characteristics, treatment patterns, and clinical outcomes among subgroups of patients with BRAF+ MM treated with dabrafenib + trametinib (dab/tram) in the United States. Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record-derived de-identified database from 1/1/2014 to 9/30/2021. Included patients were aged ≥18 years with a diagnosis of BRAF+ MM and received first-line (1L) dab/tram. Patients were stratified into 4 subgroups: high tumor burden (HTB; ≥3 sites of metastasis and lactate dehydrogenase [LDH] ≥333 IU/L), low tumor burden (LTB; <3 sites of metastasis and LDH <333 IU/L), with CNS metastases (prior to 1L dab/tram), and without CNS metastases (prior to 1L dab/tram). Patient characteristics and treatment patterns were evaluated descriptively. Given the potential patient overlap between subgroups, no comparative statistics were conducted. Real-world progression-free (rwPFS) and overall survival (OS) were explored from dab/tram initiation. Results: Among 460 included patients (mean age 60 years, 64% male), 66 (14%) had a HTB, 69 (15%) had a LTB, 164 (36%) had CNS metastases, and 296 (64%) did not. Patient characteristics were comparable across the subgroups. Over 60% of HTB patients had documented metastases in each of the liver, lung, bone, lymph nodes, and other sites. Only lung metastases had >60% prevalence among patients with a LTB. Overall, 51% of the included patients went on to receive a second-line therapy; LTB patients and those without CNS metastases had a longer time to next therapy. The median rwPFS and OS were significantly shorter among patients with a HTB vs LTB, and among patients with vs without CNS metastases (Table). Conclusions: Both tumor burden and presence of CNS metastases appear to have a significant impact on survival among BRAF+ MM patients treated with 1L dab/tram. With growing use of 1L immunotherapy in MM, 1L BRAF/MEK inhibitors are increasingly being used in patients with a worse prognosis, which may explain the lower rwPFS and OS with dab/tram when compared with clinical trials. [Table: see text]
Leveraging longitudinal clinical annotations and panel sequencing to characterize dynamics of organotropism in metastatic melanoma.
Authors: Aprati Tyler J , Manos Michael P. , Ge Will , Tarantino Giuseppe , Bai Xue , Rahma Osama E. , Gusev Alexander , Boland Genevieve Marie , Kehl Kenneth L. , Liu David
Published: June 2023

9526

Background: Although metastasis plays a major role in the mortality and morbidity of melanoma, patterns of metastasis and drivers of organotropism have not been well characterized clinically. Although previous efforts have been made to examine genomic drivers of organotropism, a longitudinal examination of metastasis dynamics has not been well characterized clinically. Methods: To address these questions, we leveraged a clinico-genomic dataset of patients with metastatic melanoma (Kehl et al. 2021). From this dataset, we assembled a cohort consisting of 26,143 artificial intelligence-annotated imaging reports from 879 patients with metastatic melanoma with an average of 2 years of followup after initial metastatic diagnosis. Annotated metastasis sites included brain, bone, adrenal, liver, lymph node, lung, and mesentery. All patients were evaluated at the Dana-Farber Cancer Institute, and each patient has at least one tumor biopsy sequenced with OncoPanel, a next-generation sequencing panel that identifies mutations in 447 cancer-related genes. Lifetime incidence of metastatic sites was defined as whether a patient ever had a report annotated with that site. Time-to-event analyses on metastatic sites used the acquisition of a metastatic site as the event of interest. For each patient index dates were defined as the date of the first scan with cancer present. We used cumulative incidence models to examine the incidence of each site in our cohort, and both cause-specific hazard models and Fine-Gray modeling to account for competing events and determine the effect of genomic covariates. Results: For lifetime metastasis status, the overall incidence varied by site, with LN being the most common, occurring in ~75% of patients, and mesentery the rarest, occurring in ~12% of patients. For lifetime metastasis status, patients with adrenal metastases were positively enriched for mutations in SETD2 (P < 0.005). Among the significant genes for all sites were many genes encoding epigenetic modifiers. In the time-to-event setting, the order of the cumulative incidence functions for each site matched the lifetime frequency of sites. Through time-to-event analysis we found genes whose mutant status were significantly associated with a change in risk and/or rate of certain metastatic sites. Among other results, we found that having a mutation in SETD2 is significantly positively associated with an increase rate and risk of adrenal metastases (cause-specific HR 2.4, P < 0.005, Fine-Gray HR 2.6, P < 0.005), and NRAS mutations were significantly associated with lower rate and risk of liver metastasis (cause-specific HR 0.59 P < 0.05, Fine-Gray HR 0.58 P < 0.01). Conclusions: By using time-to-event analysis with longitudinal metastatic annotations, we identify potential drivers of organotropism in melanoma patients.
Risk of further progression or death among durable progression-free survivors with melanoma in PD-1 blockade trials: Implications for imaging surveillance.
Authors: Deng Lei , Jiang Changchuan , Attwood Kristopher , Perimbeti Stuthi , Hu Chen , Puzanov Igor
Published: June 2023

9529

Background: Durable progression-free survivors (dPFSors) over 2 years have been reported among melanoma patients treated with PD-1 blockade. However, non-negligible risk of further progression still exists and the optimal imaging surveillance interval is unknown. Methods: Individual patient data of progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with follow-up of at least 5 years of PFS events. Co-treatment with anti-CTLA4 antibody was allowed. Patients with PFS of at least 2 years were considered as dPFSors. Conditional risk of progression or death with 95% CI was estimated based on a piece-wise exponential survival model, with the assumption that within each year from the beginning of the third year, the risk of progression/death (P/D) was constant. Conditional risks of P/D every 3, 4, 6, and 12 months in each subsequent year were calculated with 95% confidence interval (CI). We pre-specified three maximal risk levels – 10%, 15%, and 20% at each imaging scanning interval. An interval is considered as acceptable if the 95% CI upper bound of the risk at each scan is lower than a pre-specified risk level. Results: Of 1495 melanoma patients from 3 clinical trials, 474 (31.7%) were dPFSors. Among them, the PFS probability for additional 3 years was 76.4%. During the 3 years, no more than 5.0% of patients had P/D in any quarters. The yearly risk of P/D was 15.5% (95% CI 13.7% - 17.3%), 8.8% (6.8% - 10.8%), and 6.3% (3.8% - 8.8%) during the 3rd, 4th, and 5th year, respectively. Under risk at 10%, 15%, and 20%, melanoma dPFSors can be scanned every 6, 6, and 12 months during the 3rd year, every 6, 12, and 12 months during the 4th, and every 12, 12, and 12 months during the 5th, respectively. Conclusions: Based on their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding imaging surveillance schedule beyond every 3 months. [Table: see text]
A prediction model for response to immune checkpoint inhibition in advanced melanoma.
Authors: van Duin Isabella A.J. , Verheijden Rik Jasper , van Diest Paul J. , van den Eertwegh Alfonsus Johannes Maria , de Groot Jan Willem , van Not Olivier Jules , Aarts Maureen J.B. , Van Den Berkmortel Franchette , Blank Christian U. , Haanen John B. A. G. , Hospers Geke , Piersma Djura , van Rijn Rozemarijn , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Stevense - den Boer Marion , Boers-Sonderen Marye J. , Kapiteijn Ellen , Suijkerbuijk Karijn , Elias Sjoerd G.
Published: June 2023

9532

Background: Immune checkpoint inhibition (ICI) has greatly improved the prognosis for advanced melanoma in the last decade. However, it is still difficult to predict who will benefit from treatment. We aimed to develop a multivariable prediction model for response to ICI, using clinical data including primary melanoma characteristics. Methods: We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy, originating from the Dutch Melanoma Treatment Registry. The endpoint of the study was objective response to ICI within 6 months after treatment initiation. The model considered 15 candidate predictor variables, was developed with logistic regression using Akaike information criterion-informed backward selection, and was internally validated with bootstrap resampling. Performance evaluation included calibration and discrimination. We used multiple imputation to account for missing data. Results: Patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. Median follow-up time was 15 months and 1311 patients (39%) had an objective response within 6 months. The prediction model for response included sex, serum lactate dehydrogenase, World Health Organization performance score, type of systemic therapy, line of systemic therapy, stage of disease, location of primary melanoma, type of primary melanoma, satellites and/or in transit metastases at time of primary diagnosis, and time to first distant recurrence. The model was well-calibrated. The AUC was 0.664 (95% confidence interval [CI] 0.645-0.682), and the over-optimism adjusted AUC was 0.649 (95% CI 0.631-0.667). The range of predicted response probabilities was 6-78%. Based on these probabilities, patients were categorized into quartiles. The median predicted response probability was 25% (interquartile range [IQR] 21-28%) for the lowest quartile and 54% (IQR 50-59%) for the highest quartile. Compared to the lowest response quartile, patients in the highest quartile had a significant longer median PFS (19.9 versus 2.8 months; p < 0.001) and median OS (66.5 versus 8.4 months; p < 0.001). Conclusions: We present a model based on both clinical variables and primary melanoma characteristics capable of predicting response to ICI in patients with advanced melanoma. This model can discriminate between patients with a very good and very poor prognosis.
Interim results from a phase I/II study of duvelisib PI3Kδγ inhibitor and nivolumab in patients with advanced unresectable melanoma who have progressed on anti-PD1 therapy.
Authors: Jin Jingxiao , Rohatgi Anjali , Gabrielle Andrew , Rose Amy , Wilson Melissa , Bruno Tullia C. , Kirkwood John M. M.
Published: June 2023

9540

Background: The majority of unresectable melanoma patients eventually progress on first-line checkpoint blockade therapy. Duvelisib is a potent phosphoinositide 3-kinase (PI3K) δ and γ isoform inhibitor approved for relapsed/refractory CLL. PI3Kγ inhibition has been shown to restore anti-PD1 activity in preclinical tumor models through conversion of tumor associated macrophages (TAMs) from an immunosuppressive to a pro-inflammatory state. PI3Kδ inactivation has been associated with impaired T regulatory cell (Treg) function and reduced intratumoral Treg numbers. We report study design and results of a phase I study to evaluate the safety and efficacy of duvelisib and nivolumab in anti-PD1 refractory patients. Methods: Utilizing a modified 3+3 design with escalating doses of duvelisib (15 mg daily, 25 mg daily, and 25 mg BID), patients with unresectable melanoma were treated with nivolumab and duvelisib until unacceptable toxicity or disease progression. Primary endpoints for the phase I portion were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of duvelisib. Secondary endpoints include early and late toxicities and anti-tumor activity based on RECIST v1.1. Exploratory endpoints were to evaluate dose-dependent changes in the immune cell populations of peripheral blood and tumor tissue with duvelisib and nivolumab. Results: Ten patients have been enrolled (7 at dose level I, 3 at dose level II) with mean age 64. Two patients had BRAF V600E mutation and were previously treated with BRAF/MEK inhibitors. No dose limiting toxicities (DLT) were observed. Grade 3 or higher adverse events (AEs) attributable to study treatment occurred in 4 patients (40%), including G3 neutropenia (10%), G3 diarrhea (10%), G3 vomiting (10%) and G4 hepatitis (20%). Both instances of hepatitis resolved rapidly with 1-2mg/kg of prednisone. In one patient, hepatitis and nausea/vomiting led to discontinuation of treatment. Out of 6 patients who had follow-up imaging, 4 exhibited progressive disease, one stable disease, and one had partial response of 11 months duration. Given the published data on the regulation of macrophages and Tregs by PI3Kδγ inhibitors, we are utilizing multispectral imaging to measure the spatial interactions of key immune cells within the tumor microenvironment (T cells, B cells, and macrophages) in all matched pre-/post-treatment paraffin-embedded tissues, for which results will be presented. Conclusions: The combination of duvelisib and nivolumab was well-tolerated in patients with advanced unresectable melanoma refractory to ICI without DLTs to date at 15 and 25mg daily dosages. Significant anti-tumor activity was noted in one patient. Enrollment at dose level II is ongoing. Clinical trial information: NCT04688658 .
Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma.
Authors: Heinzerling Lucie , Haferkamp Sebastian , Schilling Bastian , Berking Carola , Geissler Ed , Zeman Florian
Published: June 2023

9544

Background: Patients with BRAF wildtype (wt) metastatic melanoma with primary resistance to immune checkpoint inhibitors (ICI) have a dismal prognosis. Chemotherapy has been shown to induce mutations, alter the tumor microenvironment as well as the microbiome, and modulate the immune system. This prospective phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can render ICI non-responsive patients with metastatic melanoma responsive to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) targets patients with histologically confirmed BRAFwt metastatic melanoma showing primary resistance to ICI therapy. Applying an optimal two-step design, the uninteresting responder rate was set to 5% with an expected rate of 20%. Response is defined as complete or partial response by week 14 according to RECIST 1.1. Design foresaw 29 assessable patients at first step and 38 patients overall (alpha one-sided 5%, 90% power).After showing primary resistance to ICI, patients received 2 doses of DTIC (850 mg/m2 i.v.) on days 1 and 21, and were subsequently re-exposed to the same ICI therapy they had previously shown resistance to. Results: In total, 38 patients were screened at 4 skin cancer centers. Interim analysis was performed after 29 patients who had received at least one ICI re-exposure were assessable for efficacy. Overall response rate was 24% (90%CI 12-41%) with 7 out of 29 patients showing a partial response; disease control rate was 38%. Application was well tolerated with 16% grade 3 or more adverse events and no new safety signals. Conclusions: Interim analyses results indicate that this approach of a short-term chemotherapy can break resistance in a subgroup of patients and allows us to continue the phase II trial to assess relevance of this treatment approach for metastatic melanoma. Enrolment is ongoing. Clinical trial information: NCT04225390 .
Phase II clinical trial of camrelizumab combined with famitinib for advanced acral and mucosal melanoma.
Authors: Mao Lili , Si Lu , Li Caili , Bai Xue , Dai Jie , Wei Xiaoting , Kong Yan , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Lian Bin , Wang Xuan , Tang Bixia , Li Siming , Yan Xieqiao , Zhou Li , Li Juan , Wu Xiaowen , Li Huajun , Guo Jun
Published: June 2023

9550

Background: Acral and mucosal melanoma were rarely seen in Caucasians but common in Asians. Previous studies revealed that acral and mucosal melanoma are more aggressive than cutaneous melanoma with a high unmet need for effective treatments. Camrelizumab plus anti-angiogenic agents have shown promising antitumor activity in previously untreated melanoma. Famitinib, a selective multiple-target tyrosine kinase inhibitor that exhibits both anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, PDGFR, c-kit, FGFR and so on, combined with camrelizumab had been proven effective in multiple cancers. This study aimed to assess the antitumor activity and safety of camrelizumab plus famitinib in both immunotherapy naïve and experienced advanced mucosal or acral melanoma. Methods: This single-center, open-label phase II study recruited patients (pts) with advanced acral and mucosal melanoma. Pts who were immune checkpoint inhibitors (ICI) treatment naïve were in cohort 1, while pts experienced ICI in cohort 2. In both cohorts, pts received camrelizumab (200 mg i.v. q3w) and famitinib (20 mg po qd) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. This analysis focused on cohort 2. Results: As of January 12, 2023, 18 pts (9 mucosal and 9 acral histology subtypes) were enrolled in cohort 2. The median age of all pts was 58 yrs (ranged 38-71 yrs); 9 pts (50.0%) were female; prevalence of mutations: BRAF (11.1%), C-KIT or NRAS (16.7% each); 38.9% received ≥2 prior treatments. All pts progressed after anti-PD-1/L1 monotherapy (27.8%) or combinational therapy (66.7%), except one progressed after 4-1BB mAb monotherapy. The combination drugs included anti-LAG-3/CTLA-4 antibodies (38.9%), oncolytic viruses (11.1%), c-kit inhibitors, chemotherapy and anti-angiogenic agents (5.6% each). The median follow-up was 7.3 months (ranged 4.6-14.7 months). At the data cutoff, 5 pts remained on treatment. 17 pts were evaluable. The ORR and DCR were 17.6% and 64.7%, including two pts with confirmed PR, and one with unconfirmed PR, all of which were acral subtype. The median PFS was 6.0 months. The median OS was not reached. Of 18 pts, the incidence of treatment-related adverse events (TRAEs) was 88.9%. The most common grade 3 TRAEs was neutrophil count decreased (11.1%). No grade 4 TRAEs and no treatment-related deaths occurred. Conclusions: Camrelizumab plus famitinib showed promising antitumor activity in ICI-experienced advanced acral and mucosal melanoma pts, and was generally well tolerated. Clinical trial information: NCT05051865 .