PD-L1 TPS Research Articles

Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer

ObjectivesThe impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.MethodsIn a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4–6 weeks after treatment initiation.ResultsMedian cGAS and STING H-scores were 220 (range, 5–300) and 190 (range, 0–300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.ConclusioncGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).

Comparison of immune checkpoint inhibitor plus chemotherapy or ipilimumab plus nivolumab-based therapy for NSCLC patients with PD-L1 TPS (1%–49%): TOPGAN2023-01

Comparison of immune checkpoint inhibitor plus chemotherapy or ipilimumab plus nivolumab-based therapy for NSCLC patients with PD-L1 TPS (1%–49%): TOPGAN2023-01

HER2 amplification and PD-L1 expression in invasive stratified mucin-producing carcinoma of the cervix: a clinicopathological analysis of eighteen cases

Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.

271. EFFICACY OF NEOADJUVANT CF OR DCF, FLOT PLUS NIVOLUMAB FOR RESECTABLE LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA (JCOG1804E: FRONTIER)

Abstract Background The standard neoadjuvant therapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC) in Japan is DCF (docetaxel [DTX] + cisplatin [CDDP] + 5-fluorouracil [5-FU]). In addition, neoadjuvant immune checkpoint inhibitors have shown a survival benefit for metastatic ESCC and several other cancers. We previously reported that neoadjuvant CF (CDDP + 5-FU) + nivolumab (Nivo), DCF + Nivo, and FLOT (5-FU + l-leucovorin [l-LV] + oxaliplatin [L-OHP] + DTX) + Nivo are tolerable and show promising short-term efficacy for resectable locally advanced ESCC. However, the long-term efficacy of these neoadjuvant treatments remains unclear. Methods JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant CF (cohorts A and B [adding run-in Nivo]) or DCF (cohorts C and D [adding run-in Nivo]) or neoadjuvant FLOT (cohort E) for resectable locally advanced ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer treatment. Secondary efficacy endpoints were pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS) for each treatment. Results Thirty-seven patients were enrolled (median age [range]: 62 [31-75] years; PS 0/1: 32/5; clinical stage I/II/III/IVA: 7/9/20/1; PD-L1 TPS &amp;lt;1%/≥1%/unknown: 10/26/1). In CF-based treatment cohorts (n=13), median follow-up time (range), pCR, and 3-year PFS were 42.3 (20.9-50.1) months, 7.7%, and 66.6%, respectively. The respective values for the DCF-based treatment cohorts (n=12) were 32.2 (8.0-39.8) months, 33.3%, and 83.3% and for the FLOT-based treatment cohort (n=12) were 16.2 (5.3-20.6) months, 41.7%, and 91.7%. In the overall population (n=37), median follow-up time was 31.9 (5.3-50.1) months and 3-year OS was 82.4%. Conclusion Neoadjuvant CF or DCF or neoadjuvant FLOT + Nivo followed by surgery for resectable locally advanced ESCC showed promising short- and long-term efficacy. (NCT03914443)

Induction chemotherapy backbone in frail patients with advanced NSCLC treated with chemotherapy plus pembrolizumab: a single institution retrospective audit of dose intensities from modified regimens.

Guidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population.

Homologous recombination deficiency status predicts response to immunotherapy-based treatment in non-small cell lung cancer patients.

Homologous recombination deficiency (HRD) is a biomarker that predicts response to ovarian cancer treatment with poly (ADP-ribose) polymerase (PARP) inhibitors or breast cancer treatment with first-line platinum-based chemotherapy. However, there are few studies on the prognosis of lung cancer patients treated with immune checkpoint inhibitor (ICI) therapy using HRD as a biomarker. We studied the relationship between HRD status and the effectiveness of first-line ICI-based therapy in EGFR/ALK wild-type metastatic non-small cell lung cancer patients (NSCLC) patients. This study included 22 treatment naïve NSCLC patients. The HRD score ranged from -26.37 to 92.34, with an average of 24.57. Based on analysis of the progression-free survival (PFS) data from the included NSCLC patients, threshold traversal was carried out. HRD (+) was defined as an HRD score of 31 or higher. Kaplan-Meier PFS survival analysis showed prolonged median PFS (mPFS) in NSCLC patients with HRD (+) versus HRD (-) (N/A vs. 7.0 ms, log-rank p = 0.029; HR 0.20, 95% CI: 0.04-0.96, likelihood-ratio p = 0.03). In patients with PD-L1 TPS ≥50% and HRD score ≥31 (co-status high), the mPFS was temporarily not reached during the follow-up period. In patients with PD-L1 TPS <1% and HRD score <31, the mPFS was 3 ms. Cox regression analysis showed that the hazard ratio of the co-status was 0.14 (95% CI: 0.04-0.54), which was a good prognostic factor, and the prognostic effect of co-status was better than that of HRD score alone. The HRD status can be identified as an independent significance in NSCLC patients treated with first-line ICI-based therapy.

Increased infiltration of M2-polarized tumour-associated macrophages is highly associated with advanced disease stage and high expression of PD-L1 in buccal mucosa carcinoma

ObjectiveTo assess the infiltration characteristics of tumour-associated macrophages (TAMs) in buccal mucosa carcinoma (BMC) and the correlation of these features with clinicopathological factors.Materials and methodsImmunohistochemistry was used to detect the expression of TAM-related markers (CD68, CD163, CD206), CD8+ T cell markers, PD-L1, and epidermal growth factor receptor (EGFR) in 46 patients with mucosal cancer after radical surgery. In addition, the correlation between TAM infiltration and clinical characteristics, PD-L1 expression, and EGFR expression was analysed.ResultsA high infiltration level of M2-polarized (CD206+) TAMs and M2-polarized (CD163+) TAMs was more common in stage T3–T4, N+, III–IV patients than in other patient groups (P < 0.05). The infiltration degree of M2-polarized (CD68+) TAMs was positively correlated with the PD-L1 TPS (P = 0.0331). The infiltration level of M2-polarized (CD206+) TAMs was higher in the EGFR high expression group than in the EGFR low expression group (P = 0.040).ConclusionHigh infiltration of M2-polarized TAMs is highly associated with advanced disease stage and higher expression of PD-L1 and EGFR in BMCs, suggesting that M2-polarized TAMs infiltration can serve as a potential therapeutic target.

Radiation therapy (RT)-free pembrolizumab plus chemotherapy (P+C) for PD-L1 TPS ≥50% locally advanced non-small cell lung cancer (LA-NSCLC): Primary analysis from multicenter single arm phase II study (Evolution trial; WJOG11819L).

LBA8050 Background: Standard of care for unresectable LA-NSCLC is chemoradiation therapy (CRT) followed by durvalumab (D). Survival curves of P monotherapy/P+C for PD-L1 TPS ≥50% stage IV NSCLC suggested possible comparable survival to CRT for stage III patients (pts). Moreover, some studies of neoadjuvant C+immunotherapy (I) for stage III pts have demonstrated high pathological complete response and major pathological response rates, implying potentially outstanding efficacy of C+I for earlier stage. We thus hypothesized P+C without RT in PD-L1 ≥50% LA-NSCLC pts provides a comparable efficacy to CRT followed by D while avoiding CRT-induced severe toxicities. Methods: This is a phase II study conducted by West Japan Oncology Group. P with platinum plus pemetrexed (PEM) (non-squamous) or P with carboplatin plus nab-paclitaxel (squamous) was administered every 3 weeks without RT. After four cycles of induction P+C, P with PEM (non-squamous) or P alone (squamous) was continued until progression or 2 years. The primary endpoint was 2 year-PFS rate (threshold/expected: 20%/45%). Results: Between May 2020 and February 2022, 21 pts were enrolled. Median age was 73 (range, 53-89). Stage IIIA/B/C included 11 (52%)/7 (33%)/3 (14%), respectively. Histologic subtypes were 14 (67%) adenocarcinoma, 5 (24%) squamous cell carcinoma, and 2 (10%) others. Median follow-up period was 29.9 (range, 0.3-44.2) months. Median number of P administrations was 30 (range, 1-35). The primary endpoint was met with 2-year PFS rate of 67% (90% CI: 46-83%). At the time of data cut-off, 13 (62%) of 21 pts were still progression-free. Median PFS and OS were not reached. Two-year OS rate was 85%. Centrally reviewed tumor response: 8 (38%) CR; 9 (43%) PR; 3 (14%) SD; and 1 (5%) NE were confirmed, resulting in overall response rate (ORR) of 81% and disease control rate of 95%. ORRs/2-year PFS rates of PD-L1 TPS 50-79% and 80-100% were 67%/56% and 92%/75%, respectively. Non-hematological AEs ≥grade 3 were observed in 11 (52%) pts, including: 2 (10%) pneumonitis; 2 (10%) pneumonia; 1 (5%) diarrhea; 1 (5%) ALT elevation; and 1 (5%) acute heart failure. There was one (5%) grade 5 AE (pneumonia). Conclusions: RT-free P+C provided long-lasting responses in approximately two-thirds of pts. Higher PD-L1 TPS cases achieved higher RR, including some CRs and higher 2-year PFS rate. To confirm our hypothesis that RT-free P+C can be a less toxic curative option in selected LA-NSCLC pts with PD-L1 TPS ≥50%, further data is warranted. Clinical trial information: NCT04153734 .

Dual immune checkpoint inhibition with nivolumab and ipilimumab (N+I) in patients with advanced anaplastic thyroid carcinoma (ATC).

e18075 Background: There are no standard of care therapies in advanced incurable setting for BRAF wild type (WT) ATC, &amp; after dabrafenib and trametinib (D+T) for BRAF V600E mutant ATC. We previously showed promising clinical activity of dual inhibition with N+I in exploratory cohort of 10 patients (pts) with advanced ATC in a single arm phase II clinical trial, with objective response rate (ORR) of 30% (NCT03246958, Lorch ASCO 2020). Here, we present efficacy and safety outcomes from a real-world cohort of pts with advanced ATC treated with N+I regimen. Methods: We conducted a retrospective cohort study of pts with advanced ATC (unresectable or with distant metastases, DM) who were seen at the Dana-Farber Cancer Institute (DFCI) thyroid cancer center from July 2021 to Jan 2024, received at least one dose of N+I with palliative intent &amp; completed at least one response assessment (data cutoff, 1/31/24). Pts on the DFCI clinical trial were not included. Investigator-assessed ORR (for the first N+I based treatment regimen) and immune-related adverse events (irAEs, collected till cutoff regardless of ongoing treatment) were evaluated. Results: 19 pts with advanced ATC (5: unresectable disease, 14: DM) were included, BRAF WT 12/19 (63%). Median age was 70y (range, 34-81), 68% female. ECOG PS at start was 0-1 in 14/19 (74%), 2 in 4 (21%) &amp; 3 in 1 (5%) pts. 5/19 (26%) pts received N+I concurrently with D+T; 4/5 (80%) in 2nd line after either mixed response or progressive disease (PD) on D+T. Best overall response (BOR) in N+I+D+T group was partial response (PR, 1/5, 20%) &amp; stable disease (SD, 4/5, 80%); ORR 20%. 14/19 (74%) pts received N+I, 12/14 (86%) as 1st line palliative therapy. 5 pts in N+I group (all with DM) received local therapies concurrently (1: debulking thyroid surgery, 3: radiation therapy (RT) to thyroid, &amp; 1: palliative RT to bone DM). BOR in N+I group were: complete response, CR (4/14, 28.6%); PR (3, 21.4%); SD (4, 28.6%); &amp; PD (3, 21.4%); ORR 50%. Excluding 5 pts with concurrent local therapies, ORR was 33.3% (1/9 CR, 2/9 PR).PD-L1 TPS was available for 12/19 pts (4: N+I+D+T, 8: N+I) and ≥1 in all tumors (range, 1-100). In 8 pts in N+I group, ORR stratified by PD-L1 TPS: TPS &lt;50 (range, 1-30): 0% (0/2: 1 SD, 1 PD), &amp; TPS ≥50 (range, 80-100): 83.3% (5/6: 3 CR, 2 PR, 1 PD). Any grade irAEs were observed in 16/19 (84.2%) pts. ≥Grade 3 irAEs occurred in 11/19 (57.9%) pts, most frequent were colitis (5, 26.3%), dermatitis/pruritus (3, 15.8%), myocarditis (2, 10.5%), &amp; adrenal insufficiency (2, 10.5%). There were no treatment-related deaths. Conclusions: In this largest real-world cohort study of pts with advanced ATC, N+I therapy showed high ORR of 50% (congruent with DFCI trial), albeit with high rates of iRAEs. High ORR was seen with PD-L1 TPS ≥50. Survival outcomes and genomic biomarkers, currently under investigation, will be presented at the meeting. N+I merit further investigation in an ATC focused clinical trial.

Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III NSCLC (TRAILBLAZER): Efficacy, safety and feasibility of surgical conversion outcomes from a proof-of-concept, phase 2 trial.

8082 Background: Consolidation immunotherapy after chemoradiation is the standard of care for unresectable stage III NSCLC. Addition of immunotherapy-based induction treatment may further improve outcome, partly by enabling surgery. We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 (an anti-PD-L1/TGF-β bifunctional fusion protein) with or without chemotherapy, followed by surgery or radiotherapy in unresectable stage III NSCLC and without EGFR/ ALK alterations. Methods: Patients with MDT-assessed surgically unresectable disease were given 3 cycles of neoadjuvant SHR-1701 (30 mg/kg Q3W) with or without chemotherapy (paclitaxel 175 mg/m2 Q3W + carboplatin AUC = 5 Q3W).Patients with PD-L1 TPS &lt; 50% received combination therapy (arm A) and those with PD-L1 TPS ≥50% were randomized (1:1) to receive combination therapy (arm B) or SHR-1701 alone (arm C). After reassessment by MDT, patients received either surgery or definitive radiotherapy (60 Gy/30 fractions) plus concurrent cisplatin (30 mg/m2 QW), all followed by consolidation SHR-1701 for 16 cycles. The primary endpoints were post-induction objective response rate (ORR) and 18-month event-free survival (EFS) rate. Arm A+B (patients receiving neoadjuvant chemoimmunotherapy) was the primary analysis cohort. Results: Between Nov. 20, 2020 and Jan. 27, 2022, 107 patients were enrolled (arm A/B/C, n = 88/9/10). Median follow-up was 22.2 months. In arm A+B, both primary endpoints were met, with a post-induction ORR of 58% (95% CI 47-68) and an 18-month EFS rate of 56.6% (95% CI 45.2-66.5). In arm C, the post-induction ORR was 40% (95% CI 12-74) and 18-month EFS rate was 77.1% (95% CI 34.5-93.9). 24-month overall survival rate was 78.3% (95% CI 68.0-85.7) in arm A+B and 100% in arm C. Overall, 27 (25% of 107; arm A+B/C, n = 24/3) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) MPR and seven (26%) pCR were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in resected patients and 57.3% (43.0-69.3) in those receiving radiotherapy. Across arms, all grade ≥3 TRAEs with frequency ≥10% were hematological toxicities. No new safety signals were identified. Conclusions: NeoadjuvantSHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising anti-tumor activity with a tolerable safety profile in unresectable stage III NSCLC. We provided first evidence that surgical conversion was feasible in a notable proportion of patients, and was associated with better survival outcomes. Clinical trial information: NCT04580498 .

Neoadjuvant immuno-chemotherapy in resectable non-small cell lung cancer: A retrospective cohort study.

e20077 Background: Neoadjuvant (NA) nivolumab-chemotherapy (nivo-chemo) has shown an improved survival and pathological complete response (pCR) rate, vs chemo alone, in early-stage, resectable non-small cell lung cancer (NSCLC). Nevertheless, there is a paucity of real-world data. Methods: We performed a real-world, retrospective analysis of outcomes and toxicities in patients with resectable NSCLC (stage IB-IIIA; EGFR/ALK alterations excluded) treated with three cycles of NA nivo-chemo followed by surgery at a single, tertiary-level Canadian cancer centre from September 2022 to September 2023. Results: Fifteen patients were treated with NA nivo-chemo. The median age was 70 years (range, 58 to 78) and 66% were males. 20% (n-3) and 40% (n-6) had N1 and N2 nodes, respectively. All patients completed three cycles of NA nivo-chemo. Objective response rate was 73% (n-11); including 1 complete response. Progression was noted in two patients (the CT predated initiation of treatment by more than 8 weeks in these patients). The median time to surgery was 10.6 weeks (range, 6-17.5). 80% patients (n-12) had a surgery (1 pneumonectomy, 11 lobectomies); and of these, 83% (n-10) are on surveillance while two patients had an event (death or progression). All (n-11) had R0 resection except one. 33% patients (n-5) had a pCR, including two with stage IIIA disease (PDL1 TPS &lt; 1% in three patients, PDL1 TPS ≥ 50% in two patients). 60% patients were started at a reduced chemo dose in cycle 1. 25% patients required further dose reduction. Grade 3 or 4 toxicities were seen in 25% patients (n-4) (neutropenia (n-2), febrile neutropenia (n-1) and pneumonitis (n-1)). Surgical complications were seen in 33% patients (n-5), including death in one patient due to postoperative intrathoracic bleed. Conclusions: NA nivo-chemo in resectable NSCLC is safe and associated with improved pCR rate. A few patients may progress on NA treatment or have a grade 3-5 toxicity precluding curative surgery. Hence, individualized informed decisions should be made. There is an unmet need of biomarkers/models that can predict pCR/toxicity for better patient selection. [Table: see text]

Assessment of carcinoembryonic antigen-related cell adhesion molecule 5 expression by immunohistochemistry in real-world clinical samples of non-small cell lung cancer.

e20013 Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an emerging target of antibody-drug conjugate therapy for non-small cell lung cancer (NSCLC). High expression of CEACAM5 has been reported in approximately 25% of patients with lung adenocarcinoma (Lefebvre AM, et al. Lung Cancer. 2023; 184:107356). However, CEACAM5 expression has not been systematically examined in a real-world patient population with NSCLC. In this study, we evaluated our experience in the assessment of CEACAM5 expression by immunohistochemistry (IHC) in routinely diagnosed clinical samples. Methods: We assessed the expression of CEACAM5 by IHC on clinical biopsy/resection samples of consecutively diagnosed NSCLC from September 2022 to June 2023 at our institution, using the anti-CEACAM5 clone 769 antibody assay protocol developed for tusamitamab ravtansine clinical trials. Only cases adequate for PD-L1 22C3 and Oncomine Comprehensive Assay v3 NGS assay were included. CEACAM5 expression was scored independently by three pathologists based on the method proposed by Lefebvre et al. Expression levels were categorized as high (≥ 50% tumor cells at ≥ 2+ intensity), moderate (1–49% tumor cells at ≥ 2+ intensity), and negative (0 or 1+ intensity). Interrater reliability was assessed by Kendall’s coefficient of concordance (KCC) and Fleiss’ Kappa. Discordant classification was reviewed with the final classification achieved by consensus. Association with PD-L1 TPS and NGS results was determined by Chi-squared test. Results: This study cohort consisted of 150 consecutively diagnosed NSCLC, including 133 adenocarcinomas and 17 squamous cell carcinomas. The samples were derived from both primary (n = 138) and metastatic sites (n = 12). Both membranous and cytoplasmic CEACAM5 expression was observed in neoplastic cells, but was consistently absent in nonneoplastic cells. The prevalence of consensus high CEACAM5 membranous expression was 21% (n = 32) overall, 20% in primary (n = 28) and 33% (n = 4) in metastatic sites. The level of interrater agreement across all categories was moderate (KCC = 0.77). Interrater agreement between high CEACAM5 expression versus moderate/negative categories combined was also moderate (Kappa = 0.60). Challenging features included the determination of staining intensity and mixed membranous and cytoplasmic staining pattern, and cases near the cut-offs of the defined categories. CEACAM5 expression was not associated with PD-L1 TPS (p = 0.42) or EGFR mutations (p = 0.44). Conclusions: Our data showed that approximately 20% of routinely diagnosed clinical NSCLC samples had high CEACAM5 expression by IHC. The interrater reliability on the determination of high CEACAM5 expression was moderate among the three pathologists. We highlighted the challenging aspects in the evaluation of this biomarker.

Efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine in elderly pre-treated patients with metastatic non-small-cell lung cancer.

e20556 Background: The subsequent therapy of elderly non-small cell lung cancer (NSCLC) without driver oncogene has always been a challenge due to the poor performance status and multiple comorbidities, especially in those who acquired resistance to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time which shows a better safety profile, antitumor angiogenesis, and immune modulatory effects compared with traditional chemotherapy. Here we designed an observational study to evaluate the efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine(mOV) in elderly pre-treated metastatic NSCLC. Methods: Patients aged 65 years and above who had been histologically or cytologically confirmed unresectable stage III and IV NSCLC were recruited for this study. All the pts had no EGFR mutation, ALK fusions, or ROS1 fusions and received at least one systematic treatment. Pts received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) for 6 cycles, followed by PD-1 inhibitors maintenance until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From May 2020 to June 2023, 23 pts were enrolled in the study. The median age was 70 with 18(78%) males. Median follow-up time was 22.8 months (range 3.9months-41.9months). The median PFS was 5.13 months (95%Cl: 3.1 months-7.1 months) and the median OS was 28.1 months (95%Cl: (15.2 months-NA). The ORR and DCR were 13% (95%C1: 1.44%-27.6%) and 69.6% (95%Cl: 49.2%-89.9%), respectively. The PFS (p = 0.459, HR = 0.671 95%CI 0.233-1.932) and OS (p = 0.483, HR = 1.607 95%CI 0.426-6.056) were similar between those pts who previously received immunotherapy (N = 16, 69.5%) and not. PD-L1 TPS didn’t affect the patient’s PFS (&lt;1% vs≥1%, p = 0.078, HR = 2.648 95%CI 0.895-7.835 ) and OS(&lt;1% vs≥1%, p = 0.306, HR = 2.202 95%CI 0.485-9.989). Adverse events (AEs) of any grade were observed in 20(86.9%) pts of which grade III-IV AEs occurred in 4 (17.4%) pts. These grade III-IV events consisted of interstitial pneumonia, pulmonary infection, leukopenia, and neutropenia. Immune-related adverse events (irAEs) occurred in 4 (17.4%) pts, of which grade III irAEs occurred in 2 (8.7%) patients with interstitial pneumonia. No grade 4 irAEs and grade 5 adverse events even occurred. Conclusions: The regimen of PD-1 inhibitors plus mOV for the subsequent therapy showed good overall survival benefits and safety in elderly patients with metastatic NSCLC without driver oncogene which suggests it is worth further exploration.

The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non–small-cell lung cancer (NSCLC).

TPS8116 Background: Pembrolizumab (pembro; anti–PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309–1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145–0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II–IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1–4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS ( &lt; 1% vs 1%–49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). The abstract was originally presented and published in: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281. Clinical trial information: NCT06077760 .

Clinical outcomes and post-progression retreatment in patients with metastatic NSCLC who complete two years of treatment with immune checkpoint blockade.

8633 Background: Immune checkpoint inhibition (ICI) has significantly improved survival in patients (pts) with metastatic non-small cell lung cancer (NSCLC). While ICI duration is commonly limited to two years, the optimal duration of ICI and post-progression treatment outcomes in pts who received at least two years of ICI are unknown. Methods: We conducted an international, multi-center study of pts with metastatic NSCLC treated with ICI for at least two years to characterize clinical outcomes and post-progression treatment patterns. Log-rank tests were used to test for differences in event-time distributions, and Cox proportional hazards models were used to estimate HRs. Results: We identified 255 pts with metastatic NSCLC treated with ICI alone (N=210, 82.3%) or ICI + chemotherapy (N=45, 17.7%) for least two years. Median age was 63.0, 42.4% were women, 93.0% had history of tobacco use, 79.2% had adenocarcinoma histology, 61.4% had a PD-L1 TPS ≥50%. From the start of ICI, the median time to progression (mTTP) was 6.9 years (95%CI 4.9-NR) and the median overall survival (mOS) was 9.5 years (95%CI 8.0-NR). Pts wo achieved a complete/partial response to ICI had a significantly longer mTTP (HR 0.41, P&lt;0.01) and mOS (HR 0.30, P&lt;0.01) compared to those with a best objective response of stable disease. Patients with high PD-L1 ≥50% (HR 0.6, P=0.02 vs PD-L1 &lt;50%), very high tumor mutational burden (TMB) ≥20 mut/Mb (HR 0.7, P=0.03, vs &lt;20 mut/Mb) and ever smoking status (HR 0.52, P=0.04, vs never smokers) had also significantly longer mTTP. There was no difference in mTTP (HR: 0.98, P=0.94) and mOS (HR: 0.61, P=0.06) between pts who stopped ICI at two years of treatment (N=112) and those who continued ICI beyond two years (N=143). Among 96 pts who progressed after ICI, 33.3% (N=32) received local ablative therapies (surgery or radiation), 9.3% (N=9) pts received systemic chemotherapy and 31.2% (N=30) pts received ICI retreatment. Among those retreated with ICI, the response rate was 63%, mTTP and mOS from the date of start of ICI retreatment were 22.7 (95%CI 11.2-NR), and 41.7 months (19.3-NR), respectively. Clinico-genomic predictors of response to ICI retreatment included higher TMB at baseline (15 vs 7.6 mut/Mb, P&lt;0.001), adenocarcinoma histology (94.4% vs 50.0%, P=0.01), and longer ICI treatment duration prior to retreatment (31.2 vs 24.5 months, P=0.02). Conclusions: Pts who received a minimum of two years of treatment with ICI experienced unprecedented long-term survival. There was no difference in outcomes between pts who stopped at two years compared to those who continue therapy. After completing two years of initial ICI therapy, a large fraction of pts who subsequently experience disease progression and are retreated with ICI experience an objective response, particularly those with longer duration of prior ICI treatment, higher TMB, and adenocarcinoma histology.

Predicting response of patients with NSCLC to immunotherapy using innate immune fitness (IIF) profiling.

8038 Background: Aberrant activity of AID/APOBEC deaminase enzymes can cause 'off-target' somatic mutations in cancerous cells. Mutations associated with deaminases and other mechanisms can be quantified using metrics relating to motif usage, strand bias, transitions/transversions, codon context, and amino acid changes. Collectively, these metrics form an Innate Immune Fitness (IIF) profile (US Patent 20200370124). The aim of this project was to conduct IIF profiling on a cohort of Non-Small Cell Lung Cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI), and use the IIF profiles to build and evaluate a predictive model. Methods: Whole exome and progression-free survival (PFS) data was obtained from Rizvi et al. 2015, Hellmann et al. 2018, Miao et al. 2018, Fang et al. 2019, Frigola et al. 2021, and Ravi et al. 2023 (n = 515). IIF profiles were generated using CRIS (v5.0.0; GMDx Genomics Ltd). Patients were classified as a ‘Responder’ (PFS &gt; 12 months or Complete Response; n = 148) or ‘Non-Responder’ (PFS ≤ 12 months; n = 367). Machine learning models were generated using the H2O.ai AutoML platform and evaluated using multiple rounds of cross-validation. Patient response predictions were collated for each patient and a consensus ‘IIF Score’ was calculated. Multivariable analysis of IIF Score, TMB (10mut/Mb) and PD-L1 TPS ( &lt; 1%, 1% - 50%, &gt; 50%) was conducted using a Cox proportional-hazards model. Results: The predictive accuracy of IIF Scores was 76% (Sensitivity = 58%; Specificity = 83% , NPV = 83% , PPV = 58%) with a Hazard Ratio (HR) of 0.39 (0.29-0.53; p &lt; 0.001; corrected for TMB and PD-L1). In comparison, the predictive accuracy of TMB was 67% (Sensitivity = 53%; Specificity = 79% , NPV = 79% , PPV = 44%), HR = 0.77 (0.59-1.00; p = 0.049; corrected for IIF Score and PD-L1). ‘PD-L1 &gt; 50%’ accuracy was 53% and HR = 0.64 (0.44-0.94; p = 0.023; corrected for IIF Score and TMB). The Area Under the Curve (AUC) for IIF Score was significantly higher than TMB (0.77 vs 0.70; DeLong test: p &lt; 0.001). Conclusions: IIF Score was the strongest predictor of patient response to ICI. Despite the inherent limitations of combining data from multiple cohorts, IIF Score outperformed TMB and PD-L1 in predictive accuracy, HR and AUC. With a Negative Predictive Value of 83%, these results support the use of IIF Score as a biomarker for identifying ICI Non-Responders in NSCLC patients. Research Sponsor: GMDx Genomics Ltd.

Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study.

8502 Background: Sacituzumab Tirumotecan (SKB264/MK-2870)is a TROP2 ADC developed with novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the initial results from a phase II study of SKB264 combined with KL-A167 in patients (pts) with advanced NSCLC (OptiTROP-Lung01, NCT05351788). Methods: Pts with treatment naive advanced NSCLC without actionable genomic alterations were enrolled to receive SKB264 5 mg/kg Q3W + KL-A167 1200 mg Q3W (cohort 1A) or SKB264 5 mg/kg Q2W + KL-A167 900 mg Q2W (cohort 1B) in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Results: As of 02 Jan 2024, 40 and 63 pts have been enrolled in cohort 1A and 1B. Median ages were 63/63 years; 97.5%/85.7% had ECOG PS of 1; 30.0%/33.3%, 32.5%/30.2% and 37.5%/36.5% of pts had PD-L1 expression &lt; 1%, 1%–49% and ≥ 50% of tumor cells by IHC 22C3 pharmDx assay, respectively. In cohorts 1A/1B, the most common Grade ≥ 3 treatment-related adverse events (TRAEs) were neutrophil count decreased (30.0%/30.2%), white blood cell count decreased (5.0%/17.5%), anemia (5.0%/15.9%), rash (5.0%/6.3%) and drug eruption (7.5%/0). TRAE leading to discontinuation of SKB264 occurred in 1 pt of cohort 1B due to drug hypersensitivity, and there were no treatment-related deaths. After median follow up of 14.0 mos and 6.9 mos for cohort 1A and 1B, the ORR was 48.6% (18/37, 2 pending confirmation), DCR was 94.6% and median PFS was 15.4 mos (95% CI: 6.7, NE) with 6-mo PFS rate of 69.2% for cohort 1A ; the ORR was 77.6% (45/58, 5 pending confirmation), DCR was 100% and median PFS was not reached with 6-mo PFS rate of 84.6% for cohort 1B. Additional subgroup analyses are shown in the Table. Conclusions: SKB264 in combination with KL-A167 demonstrated promising efficacy results in treatment naive advanced NSCLC with manageable safety profile. SKB264 Q2W was recommended for further investigation. A Phase 3 study of SKB264 Q2W plus pembrolizumab vs pembrolizumab in 1L metastatic NSCLC with PD-L1 TPS ≥ 50% (NCT06170788) is ongoing. Clinical trial information: NCT05351788 . [Table: see text]

TTF-1 negativity as a biomarker of outcomes to immunotherapy, chemoimmunotherapy, and KRAS G12C inhibitors in lung adenocarcinoma.

8608 Background: Thyroid transcription factor 1 (TTF-1) expression is routinely assessed in lung adenocarcinomas (LUAD) and is negative (TTF-1Neg) in 15-20% of cases. Whether these tumors differ from LUAD expressing TTF-1 (TTF-1Pos) in terms of biologic features and outcomes is unclear. Methods: Patients (pts) with LUAD and available TTF-1 expression by IHC at five institutions were included. Clinicopathologic, genomic, and outcomes data were compared according to TTF-1 expression. Results: Among 3,315 pts with LUAD, TTF-1 was negative in 15% (N=499). Compared to TTF-1Pos (N=2,816), pts with TTF-1Neg LUAD were more likely male (44% vs 38%, P=0.01), smokers (82% vs 74%, P&lt;0.001), with stage IV disease at diagnosis (76% vs 71%, P&lt;0.001), and lower median PD-L1 tumor proportion score (TPS, 1% vs 10%, P&lt;0.001). At stage IV diagnosis, TTF-1Neg cases less commonly had brain metastasis than TTF-1Pos cases (35% vs 44%, P=0.04), but more frequently had bone metastasis (53% vs 45%, P=0.03). TTF-1Neg LUAD was enriched for KRAS, STK11, KEAP1, SMARCA4, and CDKN2A mutations (q&lt;0.05), while TTF-1Pos LUAD was enriched for EGFR and MET mutations (q&lt;0.05). Compared to TTF-1Pos LUAD, TTF-1Neg LUAD had higher prevalence of KRAS G12D (12% vs 4%, P&lt;0.001) and G12V mutations (11% vs 7%, P=0.001), but similar frequency of G12C mutations (14% vs 15%, P=0.82). The association between TTF-1 and treatment outcomes was next investigated. Pts with stage III unresectable TTF-1Neg LUAD who received durvalumab after chemo-radiation (N=20), compared to TTF-1Pos cases (N=174), had shorter median progression-free survival (mPFS, 7.6 vs 24.7 months, P=0.01) and overall survival (mOS, 22.7 months vs not reached, P=0.01). Among pts with stage IV LUAD, TTF-1Neg cases treated with immune checkpoint inhibitors (N=237), compared to TTF-1Pos (N=1,161), had worse objective response rate (ORR, 17% vs 28%, P&lt;0.001), mPFS (2.5 vs 4.7 months, P&lt;0.001) and mOS (9.8 vs 20.9 months, P&lt;0.001). Similarly, pts with TTF-1Neg LUAD (N=297) treated with chemoimmunotherapy, compared to TTF-1Pos cases (N=920), had worse ORR (27% vs 42%, P&lt;0.001), mPFS (4.6 vs 8.1 months, P&lt;0.001) and mOS (11.2 vs 23.4 months, P&lt;0.001). TTF-1 negativity retained its association with worse outcomes after adjusting for treatment line, ECOG performance status, smoking status, PD-L1 TPS, STK11/ KEAP1 mutation status in multivariable cox regression models. Lastly, pts with KRAS G12C mutated TTF-1Neg LUAD treated with KRAS inhibitors (N=25), compared to TTF-1Pos (N=138), had worse ORR (12% vs 35%, P=0.03), mPFS (2.7 vs 5.9 months, P&lt;0.001), and mOS (4.4 vs 12.1 months, P&lt;0.001). After excluding mucinous LUAD cases, which are more commonly TTF-1Neg, similar results were observed. Conclusions: TTF-1 negativity identifies a unique clinicopathologic and genomic subset of LUAD with worse outcomes to diverse systemic therapies.

Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .

Abstract CT281: The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC)

Abstract Background: Pembrolizumab (pembro; anti-PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309-1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145-0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II-IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1-4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS (&amp;lt;1% vs 1%-49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). Citation Format: Jonathan D. Spicer, Santosh M. Nair, Adnan Khattak, Jay M. Lee, Michelle Brown, Robert S. Meehan, Nazly Shariati, Xuan Deng, Ayman Samkari, Jamie E. Chaft. The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281.