BACKGROUND:Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. In this article, we report the results of a phase I/Ib trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib. PATIENTS AND METHODS:This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). RESULTS:A total of 38 patients received Teliso-V (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, the ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% confidence interval 5.4 months-not reached). CONCLUSIONS:Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.

BACKGROUND:Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3-5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. PATIENTS AND METHODS:Eligible patients had ECOG performance status 0-2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. RESULTS:Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5-37.5); ORR was 32.3% (95% CI: 16.7-51.4); median PFS 5.75 months (95% CI: 2.27-9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9-9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). CONCLUSION:Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.

Purpose/Objective(s) Conventionally fractionated chemoradiation (CRT) is key in the treatment of locally advanced, unresectable non-small cell lung cancer (LA-NSCLC). Consolidation with durvalumab significantly improves survival, underscoring T cell importance. Hypofractionated radiation can also enhance systemic immunity, suggesting benefits beyond local control, though this has not been explored in LA-NSCLC. In an early-phase trial, patients with LA-NSCLC were treated with hypofractionated CRT with a PET-adapted stereotactic ablative radiotherapy boost (HyCRT-SABR). We investigated the longitudinal evolution of T-cell receptor (TCR) signatures with hypofractionation and its relationships to outcomes. Materials/Methods Data from a single-institution, nonrandomized, dose-escalated HyCRT-SABR with concurrent carboplatin/paclitaxel (pre-PACIFIC) trial for LA-NSCLC were analyzed (NCT01345851). Patients received an initial 40 Gy in 10 fractions followed by a PET-adapted SABR boost of 25 Gy (low), 30 Gy (int), or 35 Gy (high) in 5 fractions to residual PET-avid disease. Blood was collected at baseline, after 40 Gy, and 3-months after treatment for T cell receptor (TCR) beta chain sequencing (from a technology company). Associations between clinical features (stage, histology, mutations, smoking history, SABR boost) and TCR diversity metrics (Simpson's D, max productive frequency, Pielou evenness) with overall survival (OS), regional, or distant control were modeled using mutual information (MI), a quantitative measure of dependence in which higher relative rank indicates more predictive features. Results 28 patients (median [range] age, 70 (51-88) years; 57% male; 14% with stage II, 86% with stage III) were enrolled. There were no significant differences in toxicity, OS, PFS, or LC between SABR cohorts. TCR analysis was done for 17 patients (low, n = 6; int, n = 9; high, n = 1). For known prognostic clinical features, MI confirmed N/group stage and histology as the high scoring features for regional or distant control and N stage as the highest scoring for OS. SABR cohort was the low ranking, consistent with similar group outcomes. For exploratory features, MI identified TCR metrics at all timepoints as predictive. For regional or distant control, TCR metrics post 3-months outranked clinical features and metrics at baseline were of similar predictive rank as T stage, mutation status, and smoking history. For OS, TCR metrics after 40 Gy outranked all clinical features except N stage. Conclusion Our findings illustrate that TCR metrics of patients with LA-NSCLC from baseline to 3-months after hypofractionated CRT are potential predictors for overall survival and tumor control, equivalent to known prognostic clinical features. These findings may have implications for applying a hypofractionated CRT approach in the era of adjuvant durvalumab to amplify T-cell function.

Importance Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC).Objective To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost.Design, Setting, and Participants This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023.Intervention All patients first received 4 Gy x 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy x 5 fractions), 30 Gy (intermediate, 6 Gy x 5 fractions), or 35 Gy (high, 7 Gy x 5 fractions) with concurrent weekly carboplatin/paclitaxel.Main Outcome and Measure The primary outcome was to determine the MTD.Results Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively.Conclusions and Relevance This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC.

Hintergrund Osimertinib ist ein EGFR-TKI der 3. Generation, der EGFR-TKI sensitivierende und EGFR-T790M-Resistenzmutationen potent und selektiv hemmt. Osimertinib ist wirksam bei EGFRm NSCLC, einschließlich ZNS-Metastasierung. In der Primäranalyse der Phase-III-Studie ADAURA (NCT02511106) zeigte die adjuvante Gabe von Osimertinib einen signifikanten und klinisch bedeutsamen Vorteil im krankheitsfreien Überleben (DFS) gegenüber Placebo (PBO) bei Patienten mit R0-reseziertem EGFRm (Ex19del/L858R) NSCLC,±adj. Chemotherapie (CT): Stadium II–IIIA DFS HR, 0,17; 99,06% KI, 0,11, 0,26; p<0,0001; Stadium IB–IIIA DFS HR, 0,20; 99,12% KI 0,14, 0,30; p<0,0001. Wir berichten über explorative Analysen von DFS und Rezidivmustern nach 2 Jahren zusätzlichem Follow-up.

Background: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival.Patients and methods: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed.Results: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, >1%, 1%-49%, or >50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged >75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction >80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population.Conclusion: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

Osimertinib (osi) is a 3rd-gen CNS active EGFR-TKI for EGFRm NSCLC. In the Ph III ADAURA (NCT02511106) primary analysis adjuvant osi showed a significant DFS benefit vs placebo (PBO) in resected EGFRm NSCLC, with a low frequency of osi dose modifications/discontinuations and no new safety signals observed. We report exploratory analyses of long-term safety data from ADAURA.

Purpose/Objective(s)SABR is standard for medically inoperable early-stage NSCLC and results in excellent outcomes. However, rate of regional and distant failures is significant. Addition of immune check point inhibitors improve disease control and overall survival in stage III and IV NSCLC and may improve outcomes in early-stage NSCLC. We report safety and efficacy results of a phase II study of SABR with durvalumab (durva) in early-stage inoperable NSCLC.Materials/MethodsEligible patients had newly diagnosed, biopsy proven clinical stage I or IIA NSCLC defined by AJCC 7th edition. Patient had to be medically inoperable or refused surgery. There was a 15-patient safety lead-in cohort with pre-specified stopping rules based on incidence of grade 3 or 4 treatment-related toxicity. Patients were treated with one cycle of durva at the time of CT simulation, followed by SABR (54 Gy in 3, 50 Gy in 4, or 65 Gy in 10), then up to 4 cycles of durva (1500 mg Q4 wk). No stopping rules were met, but due to slow accrual, the study terminated prematurely in the randomized Phase II portion (1:1; SABR/durva: SABR). A total of 20 patients were enrolled from October 2017 - March 2020. Eighteen patients received SABR/durva and thus form the cohort for analysis. Local control (LC), progression-free survival (PFS), overall survival (OS), and lung cancer specific survival (LCSS) were assessed using the Kaplan Meier method. Incidences of acute (≤ 90 days) and late (> 90 days) treatment-related grade 3+ pulmonary, cardiac, and GI toxicities were tabulated.ResultsMedian age was 78.6 years-old with 61% male. Median follow-up time was 2.6 years. Seventy-two percent of the patients had T1 tumor and remaining had T2. Eighty-three percent of the patients had adenocarcinoma histology and remaining had squamous cell. Eighty-nine percent of the patients were former/current smokers. Seventy-eight percent of patients received all 5 cycles of durva, 1 patient received 3 cycles, and 2 patients received 1 cycle. The 1-, 2- year LC rates were 100% and 93.8%, PFS rates were 94.4% and 83.3%, and OS rates were 94.4% and 88.9%. The 2-year cumulative incidence for LCSS was 94.4%. At 2-years, stratified by median gross tumor volume (GTV), OS was 100% (GTV ≤ 7.9 mL) vs. 77.8% (GTV > 7.9 mL), p=0.07. Acute and late grade 3+ treatment-related toxicities were pulmonary (n=3, 16.7%; n=3, 16.7%), cardiac (none; n=3, 16.7%), and GI (none). There was one case of grade 4 pneumonitis. One patient retrospectively identified as having probably fibrotic lung disease at baseline died of respiratory failure, which was conservatively assessed as possibly related to study treatment.ConclusionFor early-stage NSCLC, SABR/durva resulted in excellent disease specific outcomes, including survival. Safety was promising, but this study underscored the importance of excluding patients with any fibrotic lung disease for safety and optimal interpretation of adverse event data. Results support ongoing phase III trials determining the benefit of SABR/durva in these patients.

8517 Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance < 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.

Purpose/Objective(s) A case series from China published in 2020 reported a high rate of radiation pneumonitis (RP) among 11 patients treated with concurrent thoracic radiotherapy (TRT) and osimertinib, including 9% who developed a fatal complication. We analyzed the RP rates for patients at our institution who were also treated with a similar combination for metastatic non-small cell lung cancer (NSCLC). Materials/Methods This retrospective study was performed at a single academic medical center in the US. We identified all patients who were treated with concurrent TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of RP that developed within 6 months of treatment was scored in accordance with CTCAE v5.0. Fisher's exact test and logistic regression were performed to investigate the association of pre-treatment factors with development of grade ≥2 and grade ≥3 RP. Results Sixteen patients with metastatic NSCLC were treated with concurrent TRT and osimertinib over the study time period. The treatment site of each patient's pulmonary metastases was as follows: peripheral in 4 (25%), central in 4 (25%) (within 1-2 cm of the proximal bronchial tree [PBT]), ultra-central in 7 (44%) (within 1 cm of the PBT), and mediastinal in 1 (6%). Two of 16 patients withheld osimertinib 24-48 hours before and after TRT, both of which had tumors in an ultra-central location. Patients were treated with a median dose of 50 Gy (11-65 Gy) in a median of 7.5 fractions (1-15 fractions); the median duration of TRT was 10 days (1-22 days). The median follow-up time was 13 months (1 – 61 months). Nine patients developed grade ≥2 RP (56%) with a median time to onset of 29 days (1-84 days). The severity of RP was grade ≥3 in 6 (37.5%) and grade 4 in 1 (6.3%); no patients had grade 5 RP. Of the 6 patients who developed grade ≥3 RP, 2 (33.3%) were treated with stereotactic body radiotherapy (SBRT) while 4 (66.6%) were treated with hypofractionated TRT. All patients who developed grade ≥3 RP were female. Tumor location for patients who developed grade ≥3 RP was central in 3 (50%), ultra-central in 2 (33%) and mediastinal in 1 (17%); no patients with peripheral tumors developed grade ≥3 RP. Both patients who withheld osimertinib before and after TRT did not develop RP. The association of female sex and non-peripheral tumor location with grade ≥3 RP was not statistically significant in the context of a small case series (p=0.23). RP was not associated with the use of SBRT vs hypofractionated TRT or mean lung dose. Conclusion TRT with concurrent osimertinib was associated with a high rate of RP, particularly when the site of pulmonary metastases was in a central, ultra-central, or mediastinal location. Withholding osimertinib 24-48 hours before and after TRT may mitigate this risk. These data raise safety concerns that are not currently listed in treatment guidelines. Further research is indicated to validate these findings in larger cohorts.

TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to "trapping" PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes.

Patients with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR blockade with HER2 blockade has been shown to have complete and long-term reversal of osimertinib resistance in preclinical models.

Telisotuzumab vedotin (Teliso-V) is an anti-c-Met antibody conjugated with a tubulin inhibitor, monomethylauristatin E. The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded for by the MET proto-oncogene. c-Met overexpression occurs in various solid tumors, including non-small cell lung cancer (NSCLC), and the aberrant activation of the c-Met/HGF axis contributes to tumor progression, angiogenesis, invasive growth, metastasis, and resistance to therapies.