BACKGROUND:Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS:HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION:Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING:Summit Therapeutics.

TPS8664 Background: The additionof antiangiogenic agents to standard first-line treatment with a programmed cell death protein 1 (PD-1) inhibitor and platinum doublet chemotherapy has shown efficacy in patients with metastatic non–small cell lung cancer (NSCLC). Ivonescimab is a novel tetravalent bispecific antibody that targets PD-1 and vascular endothelial growth factor. In a phase 2 trial, ivonescimab plus chemotherapy showed objective response rates (ORRs) of 71.4% and 54.2% and median progression-free survival (PFS) of 11.1 and 13.3 months in patients with metastatic squamous (SQ) and nonsquamous (NSQ) NSCLC, respectively (1). Methods: The multiregional, randomized, double-blind, phase 3 HARMONi-3 trial (NCT05899608) will compare the efficacy and tolerability of ivonescimab plus chemotherapy with pembrolizumab plus chemotherapy as first-line treatment in patients with metastatic SQ or NSQ NSCLC who have not previously received systemic treatment for metastatic disease and whose tumors have no known actionable mutations for which approved first-line therapies are available. Patients will be randomly assigned (1:1) to receive ivonescimab 20 mg/kg every 3 weeks (Q3W) or pembrolizumab 200 mg Q3W combined with chemotherapy (paclitaxel or nab-paclitaxel plus carboplatin for SQ or pemetrexed plus carboplatin for NSQ) for up to 4 cycles, followed by maintenance with ivonescimab or pembrolizumab alone for SQ or in combination with pemetrexed for NSQ for up to 24 months. Randomization will be done in blocks by histology (SQ and NSQ) and stratified by sex (female vs male), age (<65 vs ≥65 y), geographic region (East Asia vs rest of world), presence or absence of liver or brain metastases at baseline, previous PD-1 or programmed death ligand 1 (PD-L1) inhibitor treatment >6 months before the development of metastatic disease (yes vs no), and PD-L1 tumor proportion score (≥1% or <1%). The dual primary end points are overall survival and PFS (assessed by investigators per RECIST v1.1). The secondary end points are ORR, disease control rate, duration of response, safety, pharmacokinetics, and immunogenicity. Patients are being recruited in Asia, Europe, and North America, with a target enrollment of 1080 patients (45-50% SQ and 50-55% NSQ). 1. Zhang L et al, ELCC 2024, FPN: 68P. Clinical trial information: NCT05899608 .

Supplemental Figure 5: Immune Response Pathway-related Gene Sets are Enriched in Responders as Compared to Non-responders in Baseline Tumor Biopsies

Supplemental Figure 3: Decrease in Effector Tregs in Peripheral Blood in Patients Receiving BV+pembrolizumab

Supplemental Figure 4: Percent of FOXP3+ cells out of total immune cells in tumor biopsies before and during treatment.

Supplemental Table 1: Summary of Disposition

Abstract Purpose: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells that express CD30 and resensitize tumors to anti–PD-1 therapy. This study evaluated responses to BV + pembrolizumab after PD-1 therapy and explored corresponding biomarkers. Patients and Methods: A total of 55 patients with metastatic non–small cell lung cancer and 58 patients with metastatic cutaneous melanoma received ≥1 dose of BV + pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1–7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor. Results: For the secondary refractory metastatic non–small cell lung cancer cohort (RECIST v1.1), the ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (immune RECIST), the ORR was 24%, median PFS was 4.44 months, and median OS was 21.9 months. Overall, the median duration of OS follow-up was 17.2 months (95% confidence interval, 14.62–22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in T regulatory cells. Paired tumor biopsies from baseline and cycle 3 day 1 showed a trend of increased CD8 T-cell infiltration, especially in responding patients. Conclusions: BV + pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.

Purpose: Copanlisib in combination with immune checkpoint inhibitors demonstrated synergy and favorable antitumor immune responses in preclinical models. This study evaluated copanlisib plus nivolumab in adults with advanced solid tumors.Patients and Methods: In this phase Ib, nonrandomized, open-label, dose-escalation study, patients received intravenous nivolumab 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles) plus intravenous copanlisib (45 or 60 mg on days 1, 8, and 15 of each cycle) in 28-day cycles. The primary objective was to determine the MTD and/or recommended phase II dose of copanlisib plus nivolumab. Secondary objectives were safety, tolerability, and efficacy. Exploratory objectives included evaluation of potentially predictive biomarkers.Results: Overall, 16 patients were treated [copanlisib: 45 mg (n = 5); 60 mg (n = 11)]. The most common cancer types at baseline were bladder (25.0%) and oropharyngeal (18.8%) cancers. No dose-limiting toxicities were observed; copanlisib 60 mg was deemed the recommended phase II dose in combination with nivolumab 240 mg. Grade 3 and 4 treatment-emergent adverse events were reported in 56.3% and 12.5% of patients, respectively; one grade 5 event was reported (unrelated to treatment). Overall, 18.8% of patients achieved a partial response. Evaluations of potential biomarkers did not correlate with response, but copanlisib-modulated biomarker changes were observed before nivolumab administration and were consistent and dose-dependent.Conclusions: No new safety concerns were identified with this combination, and preliminary efficacy indicated an antitumor effect. Data supported an immunomodulatory effect of copanlisib, suggesting that this combination may enhance the efficacy of immune checkpoint inhibitors.Significance: The combination of copanlisib and nivolumab was well tolerated and showed antitumor effects in patients with advanced solid tumors. The number of circulating myeloid-derived suppressive cells decreased 24 to 48 hours after treatment with copanlisib. Further investigation of copanlisib and nivolumab is warranted as a novel strategy to enhance the efficacy of checkpoint inhibitors.

Supplemental Table 3: Metastatic Cutaneous Melanoma and All Patients Overall: Best Overall Response by RECIST v1.1

Supplemental Table 7: PD-L1 Subset Analysis in Patients with Metastatic NSCLC, by Combined Central Lab and Local Lab Data

Supplementary Table 2. Representativeness of Study Participants

Supplemental Table 4: Treatment-emergent ≥Grade 3 AEs by PT Occurring in ≥3% of Total Population

Supplemental Figure 2: Overall Survival (OS): Secondary Refractory Metastatic NSCLC (Cohort 2) [A] and Secondary Refractory Metastatic Cutaneous Melanoma (Cohort 4) [B] Kaplan-Meier Plot

TPS8126 Background: The addition of atezolizumab (atezo) to both induction therapy and maintenance therapy for patients with ES-SCLC has improved median progression free survival (PFS) and overall survival (New Eng J Med. 2018;379:2220-9). However, the median PFS from starting atezo maintenance was only 2.6 months (J Thoracic Onc. 2022;17:1122-9). Expression of TUSC2, a tumor suppressor gene, is absent in 41% of SCLC patients and is decreased in 100% of SCLC patients (Clin Cancer Res 2008;14(1):41–47). Quaratusugene ozeplasmid (QuarOze) gene therapy consists of a DNA plasmid expressing the TUSC2 gene encapsulated in a positively charged lipoplex which delivers the TUSC2 gene to cancer cells, restoring TUSC2 expression. Xenograft studies using a SCLC cell line in a humanized mouse model treated with a combination of QuarOze and atezo demonstrated significantly increased tumor cell killing compared to that of atezo alone. In addition, infiltration of immune cells was increased in the tumor tissue, whereas myeloid derived suppressor cells were decreased (Meraz IM et al, AACR/NCI/EORTC 2023). Thus, in this study QuarOze is added to atezo maintenance therapy with the aim of improving PFS after the start of maintenance therapy. Methods: Eligible patients have ES-SCLC and have completed 3-4 cycles of induction therapy with etoposide, a platinum agent, and atezo without disease progression, and are thus eligible for maintenance therapy. QuarOze is administered IV every 21 days in escalating dose cohorts in Phase 1 and atezo 1200 mg is also administered IV every 21 days. Dexamethasone, acetaminophen, and diphenhydramine are given prior to each treatment to prevent delayed infusion-related reactions. Efficacy is evaluated after every even cycle of treatment using RECIST 1.1 criteria. Safety is evaluated using CTCAE v5, with dose limiting toxicities generally defined as ≥Gr 3 adverse events (AEs). TUSC2 protein expression is measured by a validated immunohistochemistry assay in paraffin sections to determine if PFS is related to pretreatment TUSC2 levels. A validated assay measures pharmacokinetics in all patients. In Phase 1, two planned dose levels (0.09, and 0.12 mg/kg) of QuarOze were administered, and a standard dose escalation with 3-6 patients/dose level was used. The Phase 2 portion of the trial will enroll 50 patients which provides 80% power at a one-sided alpha level of 0.05 to detect an 18-week PFS rate of 52% compared to a historical 18-week PFS rate of 34% with atezo alone. This corresponds to a median PFS of approximately 4.3 months compared to a historical median PFS of 2.6 months with atezo alone. A Safety Review Committee (SRC) reviewed safety data at the end of each dose level of Phase 1 to make recommendations about dose escalation. The Phase 2 portion of the trial opened for enrollment in December, 2024. Clinical trial information: NCT05703971 .

TPS8655 Background: c-Met (MET) protein expression is frequently increased in NSCLC and is associated with poor prognosis. 24% of pts with NSQ EGFR wildtype (WT) NSCLC exhibit increased c-Met protein expression, ie, ≥25% 3+ via IHC. Addition of programmed cell death (ligand) 1 (PD-[L]1) inhibitors to chemotherapy (CT) has improved treatment of NSCLC regardless of PD-(L)1 expression. However, more-effective therapies are needed, particularly for pts with no known actionable genomic alterations. Temab-A is an antibody-drug conjugate comprising the c-Met protein–targeting antibody telisotuzumab and the potent topoisomerase 1 inhibitor adizutecan payload attached via a stable cleavable linker. In an ongoing phase 1 study (NCT05029882), Temab-A monotherapy demonstrated manageable safety and promising efficacy in pts with advanced/metastatic (a/m) NSQ EGFR WT NSCLC in second line and later, with an objective response rate (ORR) of 48% (23/48) across all c-Met expression levels and clinical benefit rate of 85% (41/48) (De Miguel et al. Ann Oncol . 2024;35:S805-S806). Herein, we describe a study evaluating Temab-A in combination with the PD-1 inhibitor budigalimab. Methods: This multicenter, global,open-label, phase 1b/2, randomized (in part 2) study (NCT06772623) will enroll ∼172 pts (≥18 yr) with a/m NSQ NSCLC. Eligible pts have ECOG 0 or 1, measurable disease per RECIST v1.1, and documented EGFR WT and PD-L1 status. Primary objectives are to evaluate safety and tolerability, assess efficacy as measured by ORR by blinded independent central review, and select the recommended phase 3 dose of Temab-A combined with budigalimab. Secondary objectives include assessment of efficacy outcomes (PFS, DOR, OS, and disease control rate), characterization of PK and immunogenicity, and evaluation of PD and potential predictive biomarkers. The study has 2 parts: a safety dose-escalation part 1 and a dose-optimization part 2. Part 1 enrolls ∼12 pts who have received ≤1 prior systemic therapy for a/m NSCLC, including platinum-based CT, an immune checkpoint inhibitor, or targeted therapy. Pts receive escalating doses of Temab-A IV Q3W guided by BOIN design in combination with a fixed dose of budigalimab IV Q3W. Dose-limiting toxicities are evaluated during cycle 1. Part 2 enrolls ∼160 pts who have not received prior systemic therapy for a/m NSCLC. Pts are randomized 1:1:1:1 to Temab-A at 1 of 2 doses determined in part 1 + budigalimab, to budigalimab + CT, or to SOC (pembrolizumab + CT) arms. Randomization is stratified by PD-L1 expression and history of brain metastases. Treatment continues until disease progression, intolerable toxicity, or other discontinuation criteria are met. The first dosing of the first patient enrolled is planned in March 2025. Clinical trial information: NCT06772623 .

BACKGROUND:Adagrasib is a KRASG12C inhibitor that demonstrated promising activity against KRASG12C-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRASG12C-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy. METHODS:KRYSTAL-12 is a randomised, multicentre, open-label, phase 3 trial conducted at 230 centres in 22 countries. Patients with Kirsten rat sarcoma viral oncogene homologue (KRAS)G12C-mutated locally advanced or metastatic NSCLC, who had previously received both platinum-based chemotherapy and anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy, were randomly allocated in a 2:1 ratio to receive 600 mg adagrasib (twice a day orally) or 75 mg/m2 docetaxel (every 3 weeks intravenously) using a centralised interactive web response system. Randomisation was stratified by region (non-Asia-Pacific vs Asia-Pacific) and previous treatment (sequential vs concurrent chemotherapy or immunotherapy). Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomised patients (intention-to-treat [ITT] population). Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov (NCT04685135), and is active but no longer recruiting. FINDINGS:Between Feb 23, 2021, and Nov 16, 2023, 453 patients were randomly allocated to receive adagrasib (301 [66%]) or docetaxel (152 [34%]). In each group, 298 (99%) patients received adagrasib and 140 (92%) received docetaxel. In the ITT population (median follow-up 7·2 months [95% CI 5·8-8·7]), median progression-free survival was 5·5 months (95% CI 4·5-6·7) with adagrasib and 3·8 months (95% CI 2·7-4·7) with docetaxel (hazard ratio 0·58 [95% CI 0·45-0·76]; p<0·0001). Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with docetaxel. There were four (1%) treatment-related deaths in the adagrasib group and one (1%) treatment-related death in the docetaxel group. INTERPRETATION:Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRASG12C-mutated NSCLC, without new safety signals. FUNDING:Mirati Therapeutics, a Bristol Myers Squibb company.

e20639 Background: The Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic (MYLUNG) Consortium assesses biomarker testing patterns to improve testing rates and usage of targeted therapies for patients (pts) with non-small-cell lung cancer (NSCLC) in community practice. Evangelist et al. (2024) reported molecular testing rates and treatment patterns in pts with early-stage NSCLC. We now report metastatic (m)NSCLC cohort data, including rates of KRAS testing and use of KRAS G12C -targeted therapies, which are now approved in the 2L. Methods: Pts were enrolled from Dec2020-Sep2022 at 18 community practices (76 sites) across the US Oncology Network. Rates of next-generation sequencing (NGS), KRAS testing, use of KRAS -targeted therapy, and outcomes (ongoing) were assessed in the mNSCLC cohort as of 12Dec2024. Data collection continues for a 5-year follow-up. Results: This analysis includes 556 pts with mNSCLC, 90% of whom were newly diagnosed; median age 70y (37, 90); 51% female; 85% non-squamous histology; 81% current or former smoker. The overall rate of NGS testing improved from 37% in an earlier study (2018-2020) to 73% in this study. KRAS testing was done for 429 pts (77%) and 138 pts (32%) had a KRAS mutation. Of pts with KRAS mutations, the most common variants were G12C (46%), G12V (13%), and G12D (12%). Of pts with a G12C mutation, 47 pts (75%) had biomarker testing results before 1L treatment; of those, 6 pts received KRAS -targeted therapy. Only 15 pts with G12C mutations had 2L treatment but 73% got a KRAS -targeted therapy. The rate of advancement to 2L was similar for the G12C (30%) and total mNSCLC populations (33%). Median survival follow-up in the G12C cohort was 38mo (35, 43) with additional outcomes analysis ongoing. Conclusions: KRAS G12C mutations occurred in our study at an overall rate (15%) similar to previously reported rates. Of pts with a G12C mutation, 75% had biomarker test results before starting 1L treatment and 73% of G12C mutation pts got a KRAS -targeted therapy in the 2L. Notably, KRAS -targeted therapies were approved during our study, emphasizing the impact of testing programs for treatment planning. Real-world outcomes and the high rate of attrition before 2L treatment affirm the need for early testing in this population, as current research seeks to advance KRAS -targeted therapies to the 1L. Data from this and future studies will guide interventions to improve molecular testing rates in NSCLC. Clinical trial information: NCT05644808 . Treatment course of G12C -positive pts. KRAS G12C pts (N=63) 1L 2L No treatment (n, %) 7 (11) 41 (73) † Received treatment (n, %) 56 (89) 15 (27) † KRAS -targeted therapy ‡ 6 (11) § 11 (73) ¶ Other targeted therapy ‡ 0 (0) 2 (13) IO or IO+chemo ‡ 48 (86) 0 (0) Chemo ‡ 2 (3.6) 2 (13) † Denominator = Received 1L treatment. ‡ Denominator = Received treatment in 1L or 2L, respectively. § 5 pts on a clinical trial. 1 pt off-label. ¶ Treatment in 1L: IO (9), chemo (1), and IO+ KRAS inhibitor (1).

LBA8509 Background: Adagrasib (ADA) is a potent covalent inhibitor of KRAS G12C with favorable properties such as long half-life (23 h), dose-dependent pharmacokinetics, and brain penetrance. In the phase 1/2 KRYSTAL-1 trial, ADA demonstrated deep and durable responses with promising PFS and OS in patients (pts) with previously treated KRAS G12C -mutated NSCLC. Here, we report the primary analysis from KRYSTAL-12 (NCT04685135), a randomized, open-label phase 3 trial of ADA compared with docetaxel (DOCE) in pts with KRAS G12C -mutated locally advanced or metastatic NSCLC who had previously received a platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy. Methods: Pts with KRAS G12C -mutated locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy, were randomized 2:1 (stratified by region [non-Asia Pacific vs Asia Pacific] and sequential vs concurrent chemoimmunotherapy) to receive ADA (600 mg BID orally; tablet formulation) or DOCE (75 mg/m 2 Q3W IV), with the ability to crossover to ADA upon disease progression (assessed by real-time blinded independent central review [BICR]). No washout period was required between prior anti-PD-(L)1 therapy and study treatment. Primary endpoint was PFS assessed per BICR according to RECIST v1.1. Secondary endpoints included ORR by BICR, duration of response (DOR), OS, 1-year OS rate, and safety. Results: In total, 301 pts were randomized to ADA and 152 to DOCE. Baseline characteristics were generally similar between treatment arms. With a median follow-up of 9.4 mo (data cutoff 31 Dec, 2023), the primary endpoint of PFS was significantly improved with ADA over DOCE (HR 0.58 [95% CI, 0.45–0.76]; P < 0.0001; median PFS 5.49 vs 3.84 mo). ORR by BICR was also significantly higher with ADA compared with DOCE (31.9% [95% CI, 26.7–37.5] vs 9.2% [95% CI, 5.1–15.0]; odds ratio 4.68 [95% CI, 2.56–8.56]; P < 0.0001); median DOR was 8.31 (95% CI, 6.05–10.35) vs 5.36 (95% CI, 2.86–8.54) mo, respectively. Treatment-related adverse events (TRAEs) were reported in 94.0% of pts treated with ADA and 86.4% with DOCE; grade ≥3 TRAEs occurred in 47.0% and 45.7% of pts, respectively. TRAEs led to discontinuation of ADA in 7.7% of pts and DOCE in 14.3%. Additional efficacy and safety analyses, including subgroup analyses, will be presented. Conclusions: In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS and ORR over DOCE in pts with previously treated KRAS G12C -mutated NSCLC. Safety profile of ADA was consistent with previous reports and with no new safety signals. These results further support ADA as an efficacious treatment option for pts with previously treated KRAS G12C -mutated locally advanced or metastatic NSCLC. Funding: Mirati, a Bristol Myers Squibb Company. Acknowledgements: KRYSTAL-12 was sponsored by Mirati, a Bristol Myers Squibb Company. Third-party medical writing support, under the direction of the authors, was provided by Flaminia Fenoaltea, MSc, of Ashfield MedComms, an Inizio company, and was funded by Mirati, a Bristol Myers Squibb Company. Clinical trial information: NCT04685135 .

TPS8128 Background: Treatment options are limited for patients (pts) with small-cell lung cancer (SCLC) whose disease has progressed on or after platinum-based chemotherapy. Therefore, there is an urgent need for evaluation of novel agents in this setting. Aurora kinase A (AURKA) is a key regulator of mitosis and AURKA expression is associated with worse prognosis in multiple solid tumor types. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor under investigation for treating SCLC. Phase 1/2 clinical trials of alisertib as either monotherapy or in combination with paclitaxel for relapsed/refractory solid tumors (including SCLC) reported response rates of 21–22%. The most common treatment-related grade ≥3 AEs were neutropenia, febrile neutropenia, and leukopenia. Preclinically, greater alisertib sensitivity has been reported in models with high c-Myc expression and/or loss of RB1 function. In a clinical study of alisertib + paclitaxel vs placebo + paclitaxel in SCLC, either c-Myc expression or mutation in RB1, RBL1, RBL2, or CDK6 showed strong correlation with an improvement in both PFS and OS in the alisertib arm. Methods: ALISCA-Lung1(NCT06095505) is a phase 2 study to determine whether there is a biomarker-defined population of pts with extensive-stage SCLC that derives increased benefit from alisertib monotherapy. Key inclusion criteria: ≥18 years of age; progression on or after first-line treatment with platinum-based chemotherapy + anti-PD-L1 immunotherapy; ≥1 measurable lesion per RECIST v1.1; availability of tissue sample for retrospective biomarker evaluation. Key exclusion criteria: prior treatment with AURKA-specific or pan-Aurora-targeted agents; active infection; immunocompromise; unstable brain metastases; inability/unwillingness to swallow tablets. Primary objective: to determine whether any biomarker(s) correlate with increased benefit to alisertib monotherapy. Biomarkers will be assessed by next-generation sequencing, mRNA expression analysis, and immunohistochemistry. Candidate biomarkers include, but are not limited to, RB1 loss of function, c-Myc expression, TP53mutation, AURKA expression, and SCLC molecular subtype. Secondary objectives: to determine investigator-assessed efficacy, survival, safety, and population pharmacokinetics. Eligible pts will receive alisertib 50 mg orally BID d1−7 q21d (including primary prophylaxis with G-CSF) until disease progression, unacceptable toxicity, or withdrawal of consent. All pts will undergo sparse pharmacokinetic sampling. Recruitment is underway and up to 60 pts will be enrolled at ~20 centers in the USA. Findings are anticipated to identify a biomarker-defined pt population that derives the greatest clinical benefit from alisertib. Future development of alisertib in SCLC is anticipated to focus on this biomarker-defined population. Clinical trial information: NCT06095505 .