Ou, Sai‐Hong Ignatius

e23419 Background: Current risk assessment for cancer-associated thrombosis remain suboptimal in NSCLC, likely due to unaccounted tumor-specific biology. Although ALK and ROS1-positive NSCLC share closely related structure and elevated thrombotic risk, real-world data on thromboembolic outcomes remain limited. Methods: This multicenter retrospective study was conducted using TriNetX, a global federated health research network;14 of 113 healthcare organizations contributed to analysis. Adults (≥18 years) with NSCLC ROS1 or ALK from 2012-2025 were included. Index event was defined as the first documented NSCLC diagnosis. Outcomes included cumulative incidence, Kaplan–Meier survival analysis (KMS), and event recurrence for arterial thromboembolism (ATE), deep vein thrombosis (DVT), and pulmonary embolism (PE). Analyses were conducted pre and post-propensity score matching (PSM) adjusted for age and sex. Subgroup analyses evaluated outcomes at 1, 3, 6, and ≥12 months. Results: 3,310 NSCLC patients were identified (ALK n=3,155; ROS1 n=155). Mean age was 73 years, with 52.8% female and 46.2% male; 72.5% White, 12.7% Black, 9.5% Asian; South (49%), Northeast (29%). ALK NSCLC were older than those with ROS1 (mean 68.9 vs 64.6 years, p<0.0001), with similar sex distribution. ROS1 had higher proportion of White (85% vs 72%), while ALK included more Asian and Black. Median follow-up prior to matching was 482 days for ROS1 (post-PSM:482) and 546 days for ALK (post-PSM:601) Incidence proportions in ROS1 NSCLC were 12.3% for ATE, 9.7% for DVT, and 12.9% for PE (vs. ALK: 22.6% for ATE, 12.5% for DVT, 11.8% for PE) For ATE, prior to PSM, ROS1 NSCLC demonstrated a significantly lower risk compared with ALK (16.6% vs 25.0%), with an absolute risk difference of −8.4% (95% CI −14.7 to −2.2; p=0.02) and relative risk of 0.66 (95% CI 0.46–0.96). KMS showed longer ATE-free survival in ROS1 compared to ALK (48.2% vs 44.5%, p=0.01; HR 0.60, 95% CI 0.40–0.91, p=0.04). After PSM, overall ATE risk difference did not reach statistical significance, although ROS1 continued to demonstrate lower risk (16.6% vs 25.8%; risk difference −9.2%, p=0.06). Notably, in the subgroup analyses, this significant risk difference emerged ≥12 months, with improved late ATE-free survival in ROS1(91.1% vs 80.3%, p=0.01). For VTE and PE, no significant differences in risk, survival analyses or recurrence, were observed between ROS1 and ALK before or after PSM (DVT risk: 9.2% vs 9.7% pre-PSM; 9.2% vs 10.1% post-PSM; PE: 11.2% vs 9.9% pre-PSM; 11.2% vs 8.6% post-PSM; all p>0.05). Conclusions: Arterial thromboembolism differed by oncogenic subtype, with higher ATE risk in ALK compared with ROS1-positive NSCLC, particularly ≥12-months. In contrast, no significant difference in venous thromboembolism and pulmonary embolism were observed; further validation in prospective studies is warranted.

8644 Background: RET fusions are targetable oncogenic drivers in 1-2% of non-small cell lung cancers (NSCLC). ARROW (NCT03037385) study results (final data lock May 20, 2024) supported the US FDA approval of pralsetinib, a highly potent, oral, selective RET inhibitor for metastatic RET -altered NSCLC. Here, we present final study results. Methods: ARROW was a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 included patients with RET -fusion-positive NSCLC who received 400 mg pralsetinib once daily (QD). Initially, treatment-naïve patients were not candidates for platinum-based therapy and presented with several unfavorable prognostic factors; this requirement was removed by protocol amendment in July 2019. Primary objectives were overall response rate (ORR, per RECIST v1.1) and safety. Progression-free survival (PFS) and overall survival (OS) are reported in the full efficacy population; the measurable disease population (MDP) was the primary analysis population for ORR and duration of response (DOR). Results: 281 patients with RET -fusion-positive NSCLC received pralsetinib 400 mg QD, with a median duration of treatment of 14.95 months (mos). Median age was 60 years; 46% were male. In the MDP (n=259), ORR was 70.3% (95% confidence intervals [CI]: 64.3, 75.8) and median DOR was 19.1 mos (95% CI: 14.5, 27.9; Table). In the efficacy population (N=281), median OS was 44.3 mos (95% CI: 30.9, 53.1) with median follow up of 47.6 mos (95% CI: 44.8, 49.2), and median PFS was 13.1 mos (95% CI: 11.4, 16.8). ORR (Table) and median PFS were markedly higher in the US (25.9 mos, n=64) vs. Asia (12.6 mos, n=122) or Europe (12.9 mos, n=95). In the safety population, 95% of patients experienced treatment-related adverse events (TRAEs); 66% experienced ≥grade 3. Common TRAEs included increased AST (n=128 [46%]), anemia (n=121 [43%]), increased ALT (n=98 [35%]), and hypertension (n=77 [27%]). 3 patients died due to TRAEs (pneumonia, n=2; interstitial lung disease and rhabdomyolysis, n=1 each). No new safety signals were identified with this update. Conclusions: Pralsetinib produced clinically meaningful and durable responses in patients with RET -fusion-positive NSCLC (regardless of prior therapies) with a manageable safety profile, confirming with this longer follow up previously published results. Clinical trial information: NCT03037385 . All MDP(n=259) Prior Platinum (n=130) Treatment-naive(n=106) ORR, % (95% CI) Overall 70.3(64.3, 75.8) 63.1(54.2, 71.4) 78.3(69.2, 85.7) US (n=58)77.6(64.7, 87.5) (n=31)64.5(45.4, 80.8) (n=19)100(82.4, 100) Europe (n=89)65.2(54.3, 75) (n=36)63.9(46.2, 79.2) (n=43)65.1(49.1, 79) Asia (n=112)70.5(61.2, 78.8) (n=63)61.9(48.8, 73.9) (n=44)81.8(67.3, 91.8) Median DOR, mos (95% CI) a (n=182)19.1(14.5, 27.9) (n=82)31.8(15.1, 40.4) (n=83)13.4(9.4, 21.7) Median DOR follow up, mos (95% CI) 46.8(42.3, 50.2) 50.3(46.9, 56.8) 42.3(37.4, 44.2) a Per FDA censoring rule.

Abstract Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA &gt;90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.

Abstract Background: While most EGFR-mutant NSCLC tumors are resistant to checkpoint inhibitors, a small subset has durable responses. Certain molecular subtypes of EGFR may be more responsive. There is a lack of clarity on the genomic and immune profiles of EGFR subtypes, and further elucidation of this may assist in optimally identifying those likely to respond to immune-based therapies. Methods: Profiles of 5,510 lung adenocarcinoma specimens were obtained utilizing next-generation sequencing of 592 genes (Caris Life Sciences) and categorized by EGFR subtype. PD-L1 expression (Ab: 22c3), tumor mutational burden (TMB), immune cell type fractions, and co-mutations in TP53 were assessed by EGFR subtype and compared to wild-type (WT) tumors. Results: Of the total cohort, 791 (14.4%) were EGFR-mutant (Table). Among EGFR-mutant tumors, exon 19 deletions were most common (49.7%), followed by L858R, (32.9%), exon 20 insertions (13.0%), L861Q (2.9%), and G719X (1.5%). PD-L1 positivity of each EGFR subtype as compared to WT did not vary, except for L858R tumors which had a significantly lower percentage of PD-L1 positive cases. Exon 19 deletion, L858R, and exon 20 insertion tumors were significantly less likely to have high PD-L1 or high TMB compared to WT. Among the EGFR subtypes, L861Q and G719X tumors had the greatest percentage with high TMB. TP53 co-mutations were frequent in EGFR tumors, especially among L861Q and G719X tumors. Exon 19 deletion and L858R tumors had significantly less CD8+ and greater CD4+ T cell fractions compared to WT. Neutrophil and M2 macrophage cell fractions were significantly higher in exon 19 deletion, L858R, and exon 20 insertion tumors compared to WT. Conclusions: Most subtypes of EGFR have profiles consistent with decreased immunogenicity; however L861Q and C719X tumors have a greater percentage with high TMB or TP53 co-mutations. Such features in uncommon EGFR subtypes may correlate with responsiveness to immune-based therapies and warrant further study. Tumor Characteristic EGFR WT(n=4719) Exon 19 del(n=393) L858R(n=260) Exon 20 ins(n=103) L861Q(n=23) G719X(n=12) PD-L1 positive (≥1%) 57.7% 51.0% 49.0% a 49.5% 47.8% 50.0% PD-L1 high (≥50%) 30.6% 19.7% a 18.8% a 14.4% a 21.7% 16.7% TMB high (≥10 mut/Mb) 35.3% 1.0% a 3.7% a 1.0% a 9.5% 18.2% TP53 co-mutation 53.9% 61.7% 63.6% a 59.2% a 69.6% a 83.3% a Median % cell fraction CD8+ 0.7 0.3 a 0.4 a 0.3 0.6 0.2 CD4+ 0.0 0.6 a 0.8 a 1.3 a 1.7 1.1 Neutrophils 5.5 8.0 a 7.3 a 7.8 a 7.4 6.4 M2 macrophages 5.5 6.4a 6.9a 6.7a 5.8 4.3 aq-value &lt; 0.05 when compared to EGFR WT (corrected for multiple comparisons) Citation Format: J. Nicholas Bodor, Joanne Xiu, Vinicius Ernani, Supreet Kaur, Hirva Mamdani, Pavel Brodskiy, Sai-Hong I. Ou, Patrick C. Ma, Margie L. Clapper, W. Michael Korn, Joseph Treat. Genomic and immune characteristics of EGFR subtypes in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4119.

9008 Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]

9002 Background: KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutation occurs in ̃14% of NSCLC. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib is optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), dose-dependent PK, and central nervous system penetration; it has demonstrated objective response and favorable tolerability in the Phase 1/1b setting. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRASG12C mutation. Here we report the first disclosure from all patients enrolled in Cohort A, a Phase 2 cohort with registrational intent, evaluating adagrasib given 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]), safety, PK, and exploratory correlative analyses. Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR). Results: As of the 15 October 2021 data cutoff, 116 patients with NSCLC harboring a KRASG12C mutation were enrolled and treated, with a median follow-up of 12.5 months. Baseline characteristics include median age 64 years, 65% female, and 15.5%/83.6% with ECOG PS 0/1; 98.3% of patients received adagrasib following prior treatment with immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. The ORR (by BICR) was 42.9% (48/112) and the disease control rate was 79.5% (89/112); 31 patients remain on treatment. Median DOR was 8.5 months (95% CI 6.2–13.8), median PFS was 6.5 months (95% CI 4.7–8.4), median OS was 12.6 months (95% CI 9.2–NE). Treatment-related AEs (TRAEs) of any grade occurred in 97.4% of patients, grade ≥3 TRAEs in 45.7%, 2 grade 5 TRAEs, and 8 (6.9%) TRAEs led to discontinuation. The most commonly reported (≥25%) TRAEs (any grade) were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), ALT/AST increased (27.6%/25%), blood creatinine increased (25.9%); the most commonly reported (≥5%) TRAEs (grade 3/4) were lipase increased (6%) and anemia (5.2%). Additional subgroup analyses will be presented, including selected demographics, molecular markers and sites of metastases. Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing (NCT04685135). Clinical trial information: NCT03785249.