Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: Experience with sotorasib in two French anti-cancer centers and practical guidance proposal.

INTRODUCTION: Sotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRASG12C-mutated non-small cell lung cancer (NSCLC). The most frequent grade 3 or 4 sotorasib-related adverse events (AEs) were diarrhea (4-12 %) and hepatotoxicity (10.1-15.1 %). Data is lacking about the management of these AEs, especially in patients receiving sequential anti-PD-(L)1 and sotorasib therapy. Our aim was to report the management of grade ≥ 2 sotorasib-related AEs in real-world setting and to propose practical guidance for the management of grade ≥ 2 sotorasib-related AEs and more generally KRASG12C inhibitors-related AEs. MATERIALS AND METHODS: Records from all consecutive patients who initiated sotorasib through expanded access program in two French anti-cancer centers from January 1st 2021 to April 1st 2023 were reviewed to identify and grade sotorasib-related AEs, according to NCI-CTCAE v5.0., and to collect AEs management data. Patients were included in the analysis if they presented a grade ≥ 2 sotorasib-related AE. RESULTS: From 57 patients identified, 21 met inclusion criteria including eighteen (86 %) who received sequential anti-PD-(L)1 and sotorasib therapy. Hepatotoxicity (76 %) and diarrhea (24 %) were the most common grade ≥ 2 sotorasib-related AEs. Among the 16 patients with a grade ≥ 2 hepatotoxicity, 12 (75 %) definitely discontinued sotorasib, among which 9 (56 %) after dose reductions and rechallenge, and five (32 %) received corticosteroids, allowing only one patient to resume sotorasib. Diarrhea and nausea were usually manageable and not associated with sotorasib discontinuation. We propose a step-by-step management practical guidance for sotorasib-related hepatotoxicity based on dose-reduction and careful monitoring. Liver biopsy is strongly encouraged for grade 3 and 4 hepatotoxicity to assess candidates for corticosteroids. DISCUSSION: The experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.

Comparing the Efficacy of Two Generations of EGFR-TKIs: An Integrated Drug-Disease Mechanistic Model Approach in EGFR-Mutated Lung Adenocarcinoma.

Mutationsin epidermal growth factor receptor (EGFR) are found in approximately 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to aggressive tumor growth. While tyrosine kinase inhibitors (TKIs) like gefitinib and osimertinib target this mutation, treatments often face challenges such as metastasis and resistance. To address this, we developed physiologically based pharmacokinetic (PBPK) models for both drugs, simulating their distribution within the primary tumor and metastases following oral administration. These models, combined with a mechanistic knowledge-based disease model of EGFR-mutated LUAD, allow us to predict the tumor's behavior under treatment considering the diversity within the tumor cells due to different mutations. The combined model reproduces the drugs' distribution within the body, as well as the effects of both gefitinib and osimertinib on EGFR-activation-induced signaling pathways. In addition, the disease model encapsulates the heterogeneity within the tumor through the representation of various subclones. Each subclone is characterized by unique mutation profiles, allowing the model to accurately reproduce clinical outcomes, including patients' progression, aligning with RECIST criteria guidelines (version 1.1). Datasets used for calibration came from NEJ002 and FLAURA clinical trials. The quality of the fit was ensured with rigorous visual predictive checks and statistical tests (comparison metrics computed from bootstrapped, weighted log-rank tests: 98.4% (NEJ002) and 99.9% (FLAURA) similarity). In addition, the model was able to predict outcomes from an independent retrospective study comparing gefitinib and osimertinib which had not been used within the model development phase. This output validation underscores mechanistic models' potential in guiding future clinical trials by comparing treatment efficacies and identifying patients who would benefit most from specific TKIs. Our work is a step towards the design of a powerful tool enhancing personalized treatment in LUAD. It could support treatment strategy evaluations and potentially reduce trial sizes, promising more efficient and targeted therapeutic approaches. Following its consecutive prospective validations with the FLAURA2 and MARIPOSA trials (validation metrics computed from bootstrapped, weighted log-rank tests: 94.0% and 98.1%, respectively), the model could be used to generate a synthetic control arm.

EORTC-SPECTA Arcagen study, comprehensive genomic profiling and treatment adaptation of rare thoracic cancers.

Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments. 102 patients recruited from 8 countries between July 2019 and May 2022 were evaluable: 56 with PM, 46 with TET (23 thymomas, 23 thymic carcinomas). Molecular profiling was performed on 70 FFPE samples (42 PM, 28 TET), and 32 cases on ctDNA (14 PM, 18 TET), within a median turnaround time of 8 days from sample reception. We detected relevant molecular alterations in 66 out of 102 patients (65%; 79% PM, 48% TET), 51 of 70 FFPE samples (73%; 90% PM, 46% TET), and 15 of 32 plasma samples (47%; 43% PM, 50% TET). The most frequently altered genes were CDKN2A/B, BAP1, MTAP in PM and TP53, CDKN2A/B, SETD2 in TET. The TMB was low (mean 3.2 Muts/MB), 2 PM had MSI-high status. MTB advised molecular-guided treatment options in 32 situations, for 17 PM and 15 TET patients (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program). Molecular testing and MTB discussion were feasible for patients with rare thoracic cancers and allowed the broadening of treatment options for 30% of the cases.

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions.

Neuregulin 1 (NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

eNRGy: a clinical trial of zenocutuzumab for cancer caused by NRG1 gene fusionsNRG1 gene fusions are rare mutations that cause cancer cells to grow. These fusions are found in many different types of cancer. Tumors with NRG1 gene fusions do not respond well to standard treatment options. Zenocutuzumab, or Zeno, is a treatment that is being tested to see if it can stop cancer that is growing because of NRG1 gene fusions. Here, we describe the reasoning for and design of an ongoing clinical trial (eNRGy) designed to study the efficacy (how well it works) and safety of Zeno in patients with cancer that has NRG1 gene fusions. The eNRGy trial is recruiting patients with cancer that has NRG1 gene fusions, including non-small-cell lung cancer, pancreatic cancer and others. Patients who join this trial will receive Zeno once every 2 weeks until their cancer grows. The main goal (primary end point) of this trial is to determine the percentage of patients whose tumors decrease in size by 30% or more. The eNRGy trial is currently enrolling patients. For more information, refer to ClinicalTrials.gov (Identifier: NCT02912949), visit https://nrg1.com/, or call 1-833-NRG-1234.

Comparison and Validation of Rapid Molecular Testing Methods for Theranostic Epidermal Growth Factor Receptor Alterations in Lung Cancer: Idylla versus Digital Droplet PCR.

Targeting EGFR alterations, particularly the L858R (Exon 21) mutation and Exon 19 deletion (del19), has significantly improved the survival of lung cancer patients. From now on, the issue is to shorten the time to treatment. Here, we challenge two well-known rapid strategies for EGFR testing: the cartridge-based platform Idylla™ (Biocartis) and a digital droplet PCR (ddPCR) approach (ID_Solution). To thoroughly investigate each testing performance, we selected a highly comprehensive cohort of 39 unique del19 (in comparison, the cbioportal contains 40 unique del19), and 9 samples bearing unique polymorphisms in exon 19. Additional L858R (N = 24), L861Q (N = 1), del19 (N = 63), and WT samples (N = 34) were used to determine clear technical and biological cutoffs. A total of 122 DNA samples extracted from formaldehyde-fixed samples was used as input. No false positive results were reported for either of the technologies, as long as careful droplet selection (ddPCR) was ensured for two polymorphisms. ddPCR demonstrated higher sensitivity in detecting unique del19 (92.3%, 36/39) compared to Idylla (67.7%, 21/31). However, considering the prevalence of del19 and L858R in the lung cancer population, the adjusted theranostic values were similar (96.51% and 95.26%, respectively). ddPCR performs better for small specimens and low tumoral content, but in other situations, Idylla is an alternative (especially if a molecular platform is absent).

Knowledge-based mechanistic modeling accurately predicts disease progression with gefitinib in EGFR-mutant lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is associated with a low survival rate at advanced stages. Although the development of targeted therapies has improved outcomes in LUAD patients with identified and specific genetic alterations, such as activating mutations on the epidermal growth factor receptor gene (EGFR), the emergence of tumor resistance eventually occurs in all patients and this is driving the development of new therapies. In this paper, we present the In Silico EGFR-mutant LUAD (ISELA) model that links LUAD patients' individual characteristics, including tumor genetic heterogeneity, to tumor size evolution and tumor progression over time under first generation EGFR tyrosine kinase inhibitor gefitinib. This translational mechanistic model gathers extensive knowledge on LUAD and was calibrated on multiple scales, including in vitro, human tumor xenograft mouse and human, reproducing more than 90% of the experimental data identified. Moreover, with 98.5% coverage and 99.4% negative logrank tests, the model accurately reproduced the time to progression from the Lux-Lung 7 clinical trial, which was unused in calibration, thus supporting the model high predictive value. This knowledge-based mechanistic model could be a valuable tool in the development of new therapies targeting EGFR-mutant LUAD as a foundation for the generation of synthetic control arms.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Reaching multidisciplinary consensus on the management of non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer.

INTRODUCTION: The optimal management of patients with non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer (NSCLC) remains controversial. In this modified Delphi study from France, we aimed to generate agreement through multidisciplinary decision-making on the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC. METHODS: An expert panel of 30 physicians from different specialities completed two Delphi rounds of a 76-item questionnaire, pertaining to: pathological confirmation of N2 disease; initial treatment approach; treatment approach in case of disease progression/stability following neoadjuvant chemotherapy; treatment approach taking into account various patient and tumour characteristics. Each questionnaire item was scored using a 9-point Likert scale. Consensus in agreement was achieved if ≥ 80 % of responses to a questionnaire item were scored between 7 and 9 and if the median value of the score to the item was ≥ 7. RESULTS: Regarding the pathologic confirmation of N2 disease, agreement (up to 100 %) was reached on endobronchial ultrasound/endoscopic ultrasound as the preferred method of initial mediastinal staging for paratracheal lymph nodes. There was also panellist agreement (up to 93 %) on the adoption as first-line treatment of surgery and (neo)adjuvant chemotherapy in patients with single-station disease, and of concurrent chemoradiotherapy followed by adjuvant immunotherapy in those with multi-station N2 disease. Panellists further agreed on the use of a non-surgical strategy, i.e., concurrent chemoradiotherapy with adjuvant immunotherapy, in patients with single-station N2 disease in case of: involvement of ≥ 2 mediastinal lymph nodes; disease progression following neoadjuvant chemotherapy; compromised cardiopulmonary function if compatible with radiotherapy; anticipated right pneumonectomy. CONCLUSIONS: This Delphi study reinforces the importance of multidisciplinary discussions leading to the best individual approach to the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC, a challenging heterogeneous population.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Futile lobectomies following video-thoracoscopic exploration for indeterminate pulmonary nodules: a retrospective study.

Background: Lung cancer screening is correlated with an increase in detection of small indeterminate pulmonary nodules and these nodules often require operative resection to obtain the diagnosis. In suspected early-stage lung cancer, video-assisted thoracoscopic surgery (VATS) has become the preferred option. In this context of minimally invasive surgery, diagnostic wedge resection is sometimes difficult to perform for small deep impalpable nodules. So, our purpose was to determine whether performing VATS for indeterminate pulmonary nodule increases the risk of lobectomy for benign lesions. Methods: A retrospective analysis was carried out in our center from January 2013 to January 2019 on patients who underwent resection for a solitary pulmonary nodule suspicious for cancer. Resection method, frozen section analysis, post-operative outcomes, operative and pathology reports were reviewed. Results: Six hundred fifty-one patients underwent surgical exploration for a solitary pulmonary nodule. Thirty hundred and forty-five patients underwent VATS and 306 patients underwent thoracotomy. Patients in the VATS group underwent significantly more wedge resections (P=0.012) and diagnosis of lung cancer was significantly more frequent in the thoracotomy group (P<0.001). One hundred and thirty-two patients (38.3%) in the VATS group and 60 patients (19.6%) in the thoracotomy group underwent lobectomy without frozen section analysis of the pulmonary nodule. There was no significant difference in terms of lobectomy performed for a benign lesion between the two groups. Conclusions: VATS was associated with a higher rate of benign lesion resection but was not associated with a higher rate of lobectomies for benign lesion in our study.

Diagnosis and prognosis of acute respiratory distress syndrome related to diffuse pneumonic-type adenocarcinoma: a single-center case series study.

Background: The absence of diagnosis of acute respiratory distress syndrome (ARDS) concerns 20% of cancer patients and is associated with poorer outcomes. Diffuse pneumonic-type adenocarcinoma (P-ADC) is part of these difficult-to-diagnose ARDS, but only limited data are available regarding critically ill patients with diffuse P-ADC. We sought to describe the diagnosis process and the prognosis of P-ADC related ARDS patients admitted to the intensive care unit (ICU). Methods: Single-center observational case series study. All consecutive patients admitted to the ICU over a two-decade period presenting with (I) histologically or cytologically proven adenocarcinoma of the lung and (II) ARDS according to Berlin definition were included. Clinical, biological, radiological and cytological features of P-ADC were collected to identify diagnostic clues. Multivariate logistic regression analyses were performed to assess factors associated with ICU and hospital mortality. Results: Among the 24 patients included [70 (61-75) years old, 17 (71%) males], the cancer diagnosis was performed during the ICU stay in 19 (79%), and 17 (71%) required mechanical ventilation. The time between the first symptoms and the diagnosis of P-ADC was 210 days (92-246 days). A non-resolving pneumonia after 2 (2 to 3) antibiotics lines observed in 23 (96%) patients with a 34 mg/L (19 to 75 mg/L) plasma C-reactive protein level at ICU admission. Progressive dyspnea, bronchorrhea, salty expectoration, fissural bulging and compressed bronchi and vessels were present in 100%, 83%, 69%, 57% and 43% of cases. Cytological examination of sputum or broncho-alveolar lavage provided a 75% diagnostic yield. The ICU and hospital mortality rates were 25% and 63%, respectively. The time (in days) between first symptoms and diagnosis [odds ratio (OR) 1.02, 95% confidence interval (95% CI): 1.00-1.03, P=0.046] and the Simplified Acute Physiology Score II (OR 1.16, 95% CI: 1.01-1.33, P=0.040) were independently associated with ICU mortality. Conclusions: Non-resolving pneumonia after several antibiotics lines without inflammatory syndrome, associated with progressive dyspnea, salty bronchorrhea, and lobar swelling (i.e., fissural bulging, compressed bronchi and vessels) were suggestive of P-ADC. Delayed diagnosis of diffuse P-ADC seemed an independent prognostic predictor and disease timely recognition may contribute to prognosis improvement.

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Lorlatinib for advanced anaplastic lymphoma kinase-positive non-small cell lung cancer: Results of the IFCT-1803 LORLATU cohort.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) represents a rare subset of lung cancer, with specific presentation, and multiple treatment options, including selective tyrosine kinase inhibitors (TKIs). Real-world evidence is insufficient regarding the actual real-life treatment sequences in the late line setting, and available clinical trials may not reflect real-world situation. Here, we took advantage of the French Expanded Access Program (EAP) of lorlatinib, a third-generation TKI targeting ALK and ROS1, to assess treatment sequencing, and lorlatinib efficacy and safety, in patients with ALK+ NSCLC. METHODS: All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included. Data were collected and reviewed from medical records by independent research staff of the French Thoracic Cancer Intergroup. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 208 patients included, 117 (56%) were female, 142 (69%) were never smokers, and 180 (87%) had stage IV NSCLC at diagnosis. The most frequent histology was adenocarcinoma (94%), and the median age was 60.9 years. At the time of lorlatinib initiation, 160 (77%) patients had brain metastases, and 125 (72%) were performance status 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 4%/17%/30%/49% of patients. A total of 162 (78%) patients had previously been treated with chemotherapy, 194 (93%) with a first-generation ALK-TKI, 195 (94%) with a second-generation ALK-TKI. The median follow-up from lorlatinib initiation was 23.3 months. The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively. Central nervous system objective response rate was 56%. Treatment was stopped due to toxicity in 28 patients (14%). The safety profile of lorlatinib was consistent with previously published data. CONCLUSIONS: Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC. GOV IDENTIFIER: NCT03727477.

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.

INTRODUCTION: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. METHODS: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. RESULTS: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. CONCLUSIONS: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry.

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes.

It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

Does Very Poor Performance Status Systematically Preclude Single Agent Anti-PD-1 Immunotherapy? A Multicenter Study of 35 Consecutive Patients.

Anti-PD-1 antibodies prolong survival of performance status (PS) 0-1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3-4 patients is unknown. Conse- cutive PS 3-4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3-4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1-7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41-63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1-3.2). Median OS was 4.4 months (95%CI, 0.5-8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9-14.3, p = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7-13.8, p = 0.003) predicted worse survival. PS improvement from 3-4 to 0-1 (n = 9) led to a median 43-month (95%CI, 0-102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.