BACKGROUND:Amivantamab is a bispecific, epidermal growth factor receptor (EGFR) and MET-proto-oncogene (MET)-targeting antibody with immune cell-directing activity. In the global Phase 3 PAPILLON trial, amivantamab plus carboplatin-pemetrexed (amivantamab-chemotherapy) significantly improved progression-free survival (PFS) vs chemotherapy alone in previously untreated participants with locally advanced/metastatic NSCLC with EGFR exon 20 insertions (Ex20ins). We evaluated clinical outcomes in Asian participants in PAPILLON (NCT04538664). METHODS:Participants were randomized 1:1 to amivantamab-chemotherapy or chemotherapy alone. Study endpoints for this analysis were PFS by blinded independent central review (primary), objective response rate (ORR), duration of response (DoR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety (secondary). Crossover to amivantamab monotherapy was allowed when disease progressed on chemotherapy alone. RESULTS:Among 186 participants in the Asian sub-cohort, 97 received amivantamab-chemotherapy and 89 received chemotherapy. At median follow-up of 16.6 months, median PFS (95% confidence interval [CI]) in the amivantamab-chemotherapy/chemotherapy groups was 11.5/5.6 months (hazard ratio [HR] 0.34; 95%CI, 0.23-0.49; nominal p < 0.0001) arms. The ORR was 70% vs 51% (odds ratio 2.2, 95%CI, 1.2-3.9; nominal p = 0.012), DoR 10.1 vs 5.5 months. Median PFS2 was not estimable vs 18.8 months (HR 0.46, 95%CI 0.26-0.83; nominal p = 0.008), and median interim OS not estimable vs 24.4 months HR 0.65, 95%CI 0.34-1.24; nominal p = 0.189), respectively, despite substantial (73%) crossover. Safety profiles for both arms were similar to the overall PAPILLON population. CONCLUSIONS:Amivantamab-chemotherapy demonstrated superior PFS vs chemotherapy and represents a new standard of care for first-line treatment of Asian participants with Ex20ins-mutated NSCLC.

INTRODUCTION: People undergoing chemotherapy treatment do not meet exercise guidelines, despite known benefits in reducing side effects. Barriers including treatment-related side effects, time, and limited access and education are most cited. Intra-infusion exercise - exercise whilst receiving chemotherapy infusion - may help overcome these barriers to increase exercise during this treatment phase. The EX-FUSION study evaluated the effect of intra-infusion exercise on chemotherapy side effects and physical activity behaviour. METHODS: Forty-five participants with stage I-III breast, colorectal and ovarian cancer were randomised to intra-infusion exercise or usual care for a baseline and three intervention chemotherapy cycles. The exercise group cycled on a foot bike at moderate intensity for 20-minutes whilst receiving chemotherapy infusion. Both groups received exercise education by a clinical exercise professional. Fatigue was the primary outcome, and secondary outcomes included other chemotherapy side effects such as peripheral neuropathy, physical activity, quality of life and resting heart rate. RESULTS: Adherence to the exercise program was 100% with no adverse events reported. There was an expected increase in fatigue symptoms, resting heart rate and peripheral neuropathy in both groups with each chemotherapy cycle, however no overall effects of intervention nor difference between groups in change over chemotherapy cycles were observed. There was also no difference between intervention groups in terms of physical activity or quality of life. CONCLUSION: Intra-infusion exercise has excellent adherence and does not increase chemotherapy side effects compared to usual care. Although 20-minutes of intra-infusion exercise alone did not alter exercise behaviour, the intra-infusion delivery provided an additional opportunity to exercise. Future work should investigate the effects of intra-infusion exercise on tumour blood flow, chemotherapy efficacy and relative dose intensity.

Tarlatamab with anti-PD-L1 achieved notable survival outcomes with manageable safety as maintenance therapy following 1L platinum-etoposide chemotherapy and anti-PD-L1 (1L chemo-IO) for extensive stage small cell lung cancer (ES-SCLC). In this phase 1b study (parts 2, 4, 7), the safety and efficacy of adding tarlatamab to 1L chemo-IO was assessed.

IntroductionImmune checkpoint inhibitor (ICI) therapy has become standard of care for late stage non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. However, inflammatory side eKects termed immune-related adverse events (irAEs) occur in up to 40% of ICI-treated NSCLC patients. Current approaches to alleviate irAEs include treatment with immune-suppressing corticosteroids. However, these treatments may undermine the eKicacy of ICIs by suppressing both the irAE and the anti-tumour immune response. To identify more specific therapeutic targets, a better understanding of the complex immunopathology underlying the development of irAEs in NSCLC is required.MethodsIn this study, pre-treatment blood samples were prospectively collected from 72 NSCLC patients, including 23 who subsequently developed irAEs. Of these 72 samples, PBMCs from 59 were characterised using high-parameter mass cytometry. Plasma from 30 samples was analysed using the SomaScan platform that provides in depth characterisation of over 10,000 proteins, and the plasma metabolome of 30 samples was explored using liquid chromatograph-mass spectrometry (LC-MS).ResultsA unique peripheral immunophenotype was observed in patients who subsequently developed irAEs, characterised by decreased memory B cell abundance, heightened Th2 immunity, and an increase in plasma cytokines. Investigation into baseline metabolites revealed dysregulation of fatty acid metabolism associated with development of irAEs. Analysis of additional paired PBMC (n = 17) and plasma (n = 12) samples collected early on treatment allowed exploration of the immunological, proteomic, and metabolic changes associated with irAE development. ICItreatment of patients who developed irAEs induced a significant increase in the abundance of CD8 memory cells and plasma histones. This points to the induction of a strong and potentially pathogenic immune response early following ICI treatment in patients who subsequently develop overt toxicity.DiscussionOverall, through application of a high-parameter multiomic approach, we have identified key cellular, proteomic and metabolomic features that predispose patients to developing immunotherapy toxicity. These findings provide insight into the complex biology underlying the development of ICI-related adverse events and inform potential treatment strategies.

Kaplan–Meier estimates showing OS in all trial patients with a valid baseline (detectable or non-detectable) plasma ctDNA result in A, patients from the AURA3 trial (n = 291) and B, patients from the FLAURA trial (n = 499). Censored data are indicated by tick marks. Abbreviations: CI, confidence interval; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R); HR, hazard ratio; mOS, median overall survival; NC, not calculable.

Univariable and multivariable analyses for OS from the AURA3 trial (ctDNA evaluable population, n = 291) and FLAURA trial (ctDNA evaluable population, n = 499).

Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency (P = 0.0021). Conversely, a gain-of-function RIPK2 allele known to increase NOD2 signaling was inherited by 61% of nonresponders from the same cohort, compared to 10% of exceptional responders and much higher than the population frequency (P < 0.0001). Within the overall recruited cohort of 144 NSCLC anti-PD1 patients, individuals with immune-related adverse events (irAE) had better overall survival, further improved in those with NOD2 LOF. In independent anti-PD1 monotherapy cohorts with a range of cancers, inherited NOD2 LOF was associated with complete or partial response (P = 0.0107). Experimental validation in mice showed germline Nod2 LOF enhanced therapeutic immune responses elicited by anti-PD1 monotherapy against a high mutation burden colorectal cancer, increasing tumor infiltration by effector memory CD8 T cells. Collectively these results reveal common inherited human variation in an immune tolerance checkpoint is a determinant of cancer immune responses elicited by pharmacological inhibition of another checkpoint.

Kaplan–Meier estimates showing investigator-assessed PFS in FLAURA trial patients by clearance or non-clearance of plasma EGFRm status at Weeks 3 or 6 in patients who had baseline detectable plasma EGFRm. For comparison, patients with baseline non-detectable plasma EGFRm are included. A, Osimertinib arm by Week 3 plasma EGFRm status (n = 238). B, Comparator EGFR-TKI arm by Week 3 plasma EGFRm status (n = 243). C, Osimertinib arm by Week 6 plasma EGFRm status (n = 240). D, Comparator EGFR-TKI arm by Week 6 plasma EGFRm status (n = 235). Censored data are indicated by tick marks. Abbreviations: CI, confidence interval; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R); NC, not calculable; mPFS, median PFS; TKI, tyrosine kinase inhibitor.

Representativeness of study participants

AURA3 flow diagram for ctDNA analysis (n = 291). Clearance refers to non-detectable plasma EGFRm, where EGFRm was detectable at baseline. *There were 9 patients in the osimertinib arm and 1 patient in the platinum-pemetrexed arm without a valid ddPCR result at Weeks 3 and 6; these samples were excluded from the ctDNA clearance analysis. Abbreviations: ctDNA, circulating tumor DNA; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R).

Correlation between EGFRm allelic fraction at baseline by ddPCR (Biodesix) and NGS (Guardant Health) analyses in A, patients from the AURA3 trial (n = 202) and B, patients from the FLAURA trial (n = 347). Abbreviations: ddPCR, droplet digital PCR; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R); NGS, next-generation sequencing.

INTRODUCTION:Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity. We assessed the safety and efficacy of amivantamab in participants with advanced NSCLC harboring primary MET exon 14 skipping mutations (METex14). METHODS:CHRYSALIS enrolled participants with METex14 NSCLC who progressed after or declined standard-of-care therapy. Participants received intravenous amivantamab weekly for 4 weeks and biweekly thereafter. Objective response rate, duration of response (DoR), clinical benefit rate, progression-free survival, overall survival, safety, and circulating tumor DNA were analyzed. RESULTS:Among 97 participants, 16 were treatment naive, 28 received prior treatment without MET therapies, and 53 received prior MET therapies. Objective response rate was 32% overall, 50% in treatment-naive participants, 46% in participants without prior MET therapies, and 19% in participants with prior MET therapies. In participants without prior MET therapies, amivantamab activity was observed regardless of co-occurring genomic alterations. Clinical benefit rate was 69% overall, 88% in treatment-naive participants, 64% in participants without prior MET therapies, and 66% in participants with prior MET therapies. Median DoR was 11.2 months; 61% (19/31) of the responders had DoR greater than or equal to 6 months. Median progression-free survival was 5.3 months (95% confidence interval, 4.3-7.0); median overall survival was 15.8 months (95% confidence interval, 14.6-not estimable). Most common adverse events were rash (79%) and infusion-related reactions (72%), most being grades 1 to 2 (52%). CONCLUSIONS:The safety profile was consistent with previous reports of amivantamab in EGFR-mutant NSCLC. Amivantamab demonstrated clinically meaningful and durable antitumor activity in participants with METex14 advanced NSCLC, including those who progressed on prior MET therapies.

FLAURA flow diagram for ctDNA analysis (n = 499). Clearance refers to non-detectable plasma EGFRm, where EGFRm was detectable at baseline. *There were 3 patients in the osimertinib arm and 7 patients in the comparator EGFR-TKI arm without a valid ddPCR result at Weeks 3 and 6; these samples were excluded from the ctDNA clearance analysis. Abbreviations: ctDNA, circulating tumor DNA; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R); TKI, tyrosine kinase inhibitor.

Assessment of correlation between EGFRm VAF in baseline plasma and investigator-assessed PFS in A, patients from the AURA3 trial, by treatment arm and B, patients from the FLAURA trial, by treatment arm. Abbreviations: CR, complete response; EGFRm, epidermal growth factor receptor mutation (ex19del or L858R); NE, not evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VAF, variant allelic fraction.

ABSTRACT Background Oncogene‐driven metastatic non‐small cell lung cancer (mNSCLC) is associated with poor survival outcomes, despite advancements in first‐line tyrosine kinase inhibitor (TKI) therapies. Aims This study aimed to characterise second‐line treatment strategies for epidermal growth factor receptor (EGFR)‐driven mNSCLC, and to evaluate associated clinical outcomes using real‐world data. Materials The EnRICH study prospectively collected clinical data on patients diagnosed with lung cancer from NSW, Australia. Patients with EGFR‐driven mNSCLC who received second‐line therapy following progression on first‐line EGFR‐TKI were included in this analysis. Outcomes assessed included progression‐free survival (PFS2) and overall survival (OS), measured from second‐line treatment. Results Of 2000 patients with newly diagnosed lung cancer, between 2016 and 2021, 1720 had NSCLC and 679 had metastatic disease. Among these, 647 underwent molecular testing, with 133 harboring an EGFR mutation. Of these 133, 80 patients received first‐line TKI therapy. From this group, 68 who subsequently received second‐line treatment following disease progression on first‐line TKI were included in this analysis. Of these 68 patients, 77% (n = 52/68) were treated with a first‐ or second‐generation TKI (Erlotinib: n = 39, Gefitinib: n = 7, Afatinib: n = 6) in the first‐line setting. The remaining 16 patients received the third‐generation TKI Osimertinib. Of the total 68 patients in this cohort, in the second‐line setting, 45 patients underwent a change in their systemic therapy, and the remaining 23 patients received radiotherapy either with cessation of first‐line TKI (n = 11) or in addition to continuation of first‐line TKI (n = 12). Of the 45 patients who underwent a change in their systemic therapy, 32 received systemic therapy alone in the second‐line setting and 13 received radiotherapy in addition to a change in systemic therapy. Of these 45 patients, 33 received a TKI, with the majority receiving Osimertinib (n = 28). Median PFS2 was 3.0 months (95% CI: 1.32–5.49), with no significant difference between patients treated with second‐line TKI and those receiving other therapies (p = 0.24). Median OS was 15.0 months (95% CI: 13.24–23.66) and similarly did not differ significantly between second‐line TKI and alternative treatment strategies (p = 0.17). Conclusions Using real‐world data from EnRICH, this represents the largest retrospective analysis of this cohort in Australia and largely predates first‐line Osimertinib use. Findings reveal a trend toward second‐line Osimertinib use, even after first‐line TKI, without significant differences in survival. There, however, remains significant heterogeneity in approaches. The lack of robust second‐line data, however, highlights the need for investigating novel therapeutic approaches.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively. Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were doselimiting toxicity (DLT) and con firmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: In the avelumab plus lorlatinib group ( ALK-posi- tive; n 1 / 4 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group ( ALK -negative; n 1 / 4 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses). Conclusions: Avelumab plus lorlatinib treatment in ALK - positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK -negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. ClinicalTrials.gov identi fi er: NCT02584634 Copyright (c) 2024 by the International Association for the Study of Lung Cancer. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Tarlatamab, a bispecific T cell engager (BiTE®) immunotherapy targeting delta-like ligand 3 (DLL3), showed durable antitumor activity and manageable safety in previously treated SCLC. Here we report long-term outcomes and intracranial activity from the DeLLphi-300 phase I study. Tarlatamab was evaluated in patients (pts) with previously treated SCLC. Pts with treated, stable brain metastases were eligible. Primary endpoint was safety. Secondary endpoints included objective response rate (ORR) per mRECIST 1.1 by investigator, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). In retrospective exploratory analyses, CNS tumor sum of diameters (SOD) was assessed per mRANO-BM by BICR in pts with ≥ 1 brain lesion at baseline. This report, with data cutoff (DCO) 14.5 months (mos) beyond Paz-Ares, J Clin Oncol 2023, includes fully enrolled cohorts of pts treated with clinically relevant doses (≥ 10 mg) of tarlatamab. 152 pts were treated with tarlatamab ≥ 10 mg (follow-up range 0.2–34.3 mos; median 12.1 mos). Across cohorts, ORR was 25.0% with mDOR of 11.2 mos (table). 25 pts had treatment duration ≥ 52 weeks (range 52–150), including 8 pts treated ≥ 104 weeks. mPFS and mOS were 3.5 mos and 17.5 mos, respectively, with PFS and OS estimates at 12 mos of 16.7% and 57.9%. Of 16 pts with a baseline CNS lesion ≥ 10 mm, CNS tumor SOD decreased ≥ 30% in 10 pts (62.5%). Of 8 pts who completed brain radiotherapy (RT) ≥ 50 days before tarlatamab initiation, 3 pts (37.5%) had ≥ 30% decrease in CNS tumor SOD. No new safety signals were identified. Table: 195MOORRmDORmPFSmOS% (95% CI)mos (95% CI)Tarlatamab (N = 152)a25.0 (18.3, 32.7)11.2 (6.6, 22.3)3.5 (2.7, 3.8)17.5 (11.4, NE)10 mg (n = 17)b35.3 (14.2, 61.7)14.9 (3.0, NE)4.0 (1.6, 11.0)20.3 (5.1, NE)30 mg (n = 8)b12.5 (0.3, 52.7)3.8 (NE, NE)1.8 (1.1, NE)7.2 (1.5, NE)100 mg (n = 76)b19.7 (11.5, 30.5)22.3 (5.6, NE)3.7 (1.9, 4.5)17.5 (11.7, NE)100 mg (eIV) (n = 32)c37.5 (21.1, 56.3)6.5 (3.5, 11.2)3.8 (1.7, 5.7)12.6 (7.9, NE)Other (n = 19)d21.1 (6.1, 45.6)NE (6.8, NE)2.8 (2.1, 3.5)NE (6.0, NE)aDCO 2 Oct 2023 b1-step dosing: 1 mg (Day 1); target dose: Days 8, 15, then Q2W cCohorts: 30 mg eIV → 100 mg Q2W; 100 mg eIV → 100 mg Q2W dCohorts: 1 → 25 → 100 mg Q2W; 1 → 100 → 200 mg Q3W; 1 → 100 mg D1/D8 eIV, extended IV; NE, not estimable Open table in a new tab aDCO 2 Oct 2023 b1-step dosing: 1 mg (Day 1); target dose: Days 8, 15, then Q2W cCohorts: 30 mg eIV → 100 mg Q2W; 100 mg eIV → 100 mg Q2W dCohorts: 1 → 25 → 100 mg Q2W; 1 → 100 → 200 mg Q3W; 1 → 100 mg D1/D8 eIV, extended IV; NE, not estimable In longer follow-up of DeLLphi-300, tarlatamab demonstrated durable responses and unprecedented survival outcomes in previously treated SCLC. While limited to analyses of treated, stable brain metastases, CNS tumor shrinkage following tarlatamab therapy and long after RT supports further study of intracranial efficacy of tarlatamab.