Squamous Non-small Cell Lung Cancer Research Articles

JK5G postbiotics attenuate immune-related adverse events in NSCLC patients by regulating gut microbiota: a randomized controlled trial in China.

This study aimed to evaluate the effects of JK5G postbiotics to regulate imbalanced gut microbiota and its impacts on the efficacy and incidence rate of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). This randomized, double-blind, placebo-controlled trial was conducted in China and included non-squamous or squamous NSCLC patients without EGFR, ROS1, and ALK alteration, treatment-naive, and stage IIIb-IV. Patients were randomly (1:1) divided into two groups to receive four cycles (three weeks for each cycle) of programmed cell death-1 (PD-1) plus chemotherapy plus placebo (control group, n = 30) or to receive PD-1 plus chemotherapy plus JK5G postbiotics (JK5G group, n = 30). The primary endpoint was objective response rate. The secondary endpoints were quality of life (QoL), adverse effects, and the 16S DNA sequencing of gut microbiota, blood inflammatory cytokines, and lymphocyte subsets. This study was registered at www.chictr.org.cn (ChiCTR2200064690). Sixty patients were enrolled. The objective response rate was 36.67% (11/30) in the control group and 50.00% (15/30) in the JK5G group (p = 0.297). The JK5G group had better QoL and nutritional levels, as well as lower depression symptoms than the control group (all p < 0.05). Moreover, the JK5G group had a lower incidence of anemia (63.33% vs. 13.33%, p < 0.001), decreased lymphocyte count (20.00% vs. 0%, p = 0.010), decreased appetite (53.33% vs. 16.67%, p = 0.003), nausea (33.33% vs. 6.67%, p = 0.010), and asthenia (30.00% vs. 6.67%, p = 0.017) than the control group. Moreover, JK5G attenuated gut microbiota imbalance, accompanied by increased Faecalibacterium, Ruminococcaceae, and fecal butyrate concentration, and diminished Escherichia-Shigella. Furthermore, JK5G administration significantly decreased the levels of pro-inflammatory markers, including TNF-α, IL-2, and C-reactive protein (CRP) (all p < 0.05). Significant increases in CD3+CD4+ T cells and CD4/CD8 ratio were observed in the peripheral blood of JK5G group patients (all p < 0.05). The enterotype data showed that patients were clustered into Blautia (E1) and Escherichia-Shigella (E2) enterotypes, and JK5G postbiotics intervention might be related to enterotype modulations. Our current findings indicated that JK5G postbiotics might attenuate irAEs, and enhance the QoL and nutrition levels of advanced NSCLC patients who received ICIs. JK5G postbiotics could also improve the gut microbiota structures and ameliorate the tumor microenvironment andinflammation. www.chictr.org.cn, identifier ChiCTR2200064690.

Cost-effectiveness of camrelizumab plus chemotherapy in advanced squamous non-small-cell lung cancer.

Objectives: A cost-effectivenessstudyof camrelizumab plus chemotherapy for advanced squamous non-small-cell lung cancerin China was conducted versus chemotherapy alone. Methods: Survival data were derived from CameL-Sq. Cost-effectiveness is indicated by an incremental cost-effectiveness ratio (ICER) less than the willingness-to-pay threshold. The partitioned survival model stability was assessed by sensitivity analyses. Results: With camrelizumab plus chemotherapy, quality-adjusted life years increased by 0.83, and cost increased by $21,259/patient versus chemotherapy. The ICER was $25,674/quality-adjusted life year. The probability of cost-effectiveness was >90% regardless of PD-L1 expression level. Regardless of the variation in each parameter across a wide range, the ICER never transcended the willingness to pay. Conclusion: Camrelizumab plus chemotherapy is a cost-effective first-line treatment for advanced squamous non-small cell lung cancer in China.

3H-3000, AN FGFR2B-SPECIFIC MONOCLONAL ANTIBODY, SHOWS SUPERIOR TUMOR KILLING IN VIVO

Abstract Background and significance Fibroblast growth factor receptor 2b (FGFR2b), a splice isoform of FGFR2, is found to overexpress across multiple cancers types and promotes dysregulated tyrosine kinase activation, resulting in tumor cell proliferation and unchecked malignancy. Cohort studies reveal FGFR2b overexpression and/or amplification in Gastric cancer (~30.2%), squamous non-small cell lung cancer (~20.8%), and endometrial carcinoma (~40%). About 80–85% patients who have advanced HER2-negative gastro-esophageal cancer undergoes approximately 12-14 months of median overall survival (mOS). Thus, there is an urgent need for novel and effective molecular targeted agents. With the recent advancement of mechanistic studies, however, FGFR2b is becoming the optimal target of multiple modalities such as mAb, bispecifics, or antibody-drug conjugate. Bemarituzumab, a FGFR2b blocking antibody, developed by Five Prime clinically demonstrates the safety of FGFR2b target and exhibits preliminary efficacy in advanced GE/GEJ adenocarcinoma patients with overexpression of FGFR2 in at least 5% or 10% of tumor cells. 3H Pharmaceuticals developed a FGFR2b-specific mAb, 3H-3000, of high-affinity, differentiated epitope and enhanced ADCC effect for FGFR2b-overexpressing gastric cancer or other FGFR2b-associated cancer types. In the meantime, we will also explore the versatility of this mAb in other format and in the combination with small molecules that will bring about a wider therapeutic spectrum. Method and Result 3H-3000 is a humanized IgG1kappa antibody with a single digit nM affinity for FGFR2b and no binding to other FGFR2 isoforms. 3H-3000 shows potent proliferation-inhibitive effects on FGFR2b-overexpressing human tumor cells. In gastric cancer cell line SNU16, 3H-3000 can fully inhibit FGF7-induced phosphorylation of FGFR2b and SNU16 proliferation in vitro. On top of signaling blocking, we strongly believe efficacy of antibody-dependent cell cytotoxicity (ADCC) is another viable mechanism for growth factor-targeting therapy. Therefore, 3H-3000 was further engineered with a 20-fold ADCC enhancement which is validated through a CD16-F158 variant-based reporter system. In FGFR2b-overexpressing human gastric cancer SNU16 or OCUM-2M xenograft model, 3H-3000 was shown to inhibit tumor growth and even induce regression, which is rather unexpected given the relative low expression of FGFR2b on SNU16 and none of the competitors exhibit similar phenomenon. With potent efficacy of tumor inhibition and killing, and excellent biophysical characteristics and developability of 3H-3000, we expect to push the molecule to clinical development in the middle of 2024. Conclusion 3H-3000 is a potent FGFR2b blocker with well-defined ADCC efficacy enhancement. It demonstrates strong blocking activity of FGFR2 signaling, strikingly enhanced ADCC activity in vitro and potent efficacy of tumor inhibition in vivo. These data strongly support its clinical development in FGFR2b-overexpressing cancers. In parallel, 3H Pharmaceuticals are also developing FGFR2- selectively tyrosine kinase inhibitors targeting FGFR2 mutations or fusion. We propose a combination of small molecule FGFR2 inhibitors and mAb of FGFR2b specificity will significantly broaden the therapeutic spectrum of heterogenous tumors where mechanism is centered around FGFR2b alteration including mutation, fusion, and overexpression.

The Cost-Effectiveness of Sugemalimab Plus Chemotherapy as First-Line Treatment for Metastatic Squamous and Non-squamous NSCLC in China.

Sugemalimab is the first China-developed programmed death-ligand 1 inhibitor that has proved to be effective as a first-line treatment for both metastatic squamous and non-squamous non-small cell lung cancer (NSCLC) when used in combination with chemotherapy. This study compared the cost-effectiveness of sugemalimab plus chemotherapy (sugema + chemo) with placebo plus chemotherapy (placebo + chemo) among metastatic squamous and nonsquamous NSCLC, respectively. Separate Markov models were constructed to generate the cumulative healthcare costs and quality-adjusted life-years (QALYs) associated with two treatment strategies over a 20-year time horizon. Transition probabilities were estimated using survival data reported in the GEMSTONE-302 trial. Health state utilities and costs were derived from published literature, national databases, and local general hospitals. Sensitivity analyses were performed to test the robustness of our conclusions. Compared with first-line placebo + chem, sugema + chemo achieved an incremental cost-effectiveness ratio (ICER) of $57,842/QALY for patients with metastatic squamous NSCLC and achieved an ICER of $78,249/QALY for patients with metastatic non-squamous NSCLC. In our sensitivity analyses of a willingness-to-pay (WTP) threshold of $35,663 per QALY, the first-line sugema + chemo was only cost-effective for patient groups when the price of sugemalimab decreased. Sugema + chemo was not cost-effective as a first-line treatment for either metastatic squamous or metastatic nonsquamous NSCLC in Chinese patients compared with placebo + chemo. However, we found that sugema + chemo would be cost-effective in patients withmetastatic squamous and non-squamous NSCLC when sugemalimab's price was decreased by > 39.0% and 64.8%, respectively.

Safety and efficacy of atezolizumab in Chinese patients with previously treated locally advanced or metastatic non-small cell lung cancer: An open-label, single-arm, multicenter study

ObjectivesTo evaluate the long-term safety and efficacy of atezolizumab monotherapy in Chinese patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC). Materials and MethodsIn this open-label, single-arm, multicenter study, patients received atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle. The primary endpoint was incidence of atezolizumab-related serious adverse events (SAEs). Secondary endpoints included other safety and efficacy measures. Patients with available tumor tissue and blood samples underwent biomarker analyses. Patients with available tumor biopsies underwent exome sequencing. ResultsThe safety and evaluable populations included 101 and 97 patients, respectively. Exome sequencing data were available for 31 patients. Median follow-up time was 27.43 months. Atezolizumab-related SAEs and immune-related adverse events occurred in 25.7% and 47.5% of the safety population, respectively, and in the following subgroups: central nervous system metastases (n = 14), 35.7% and 35.7%; squamous NSCLC (n = 39), 33.3% and 53.8%. The 24-month overall survival rate was 37.4%. Median overall survival and progression-free survival by RECIST v1.1 were 15.31 and 2.86 months, respectively; objective response rate was 16.5% in the evaluable population. PRRC2C (odds ratio: 12.780, P = 0.014) and ZMYND8 (odds ratio: 19.963, P = 0.016) gene mutations were significantly enriched in atezolizumab responders vs non-responders. Patients with CD8+ TILs > 10% vs ≤ 10% were significantly more likely to be atezolizumab responders. ConclusionNo new safety concerns were raised, and clinically meaningful benefits of atezolizumab monotherapy were shown. The results of the biomarker analyses may guide future therapeutic strategies.

Improving the turnaround time of molecular profiling for advanced non-small cell lung cancer: Outcome of a new algorithm integrating multiple approaches

BackgroundMolecular tumor profiling to identify oncogenic drivers and actionable mutations has a profound impact on how lung cancer is treated. Especially in the subgroup of non-small cell lung cancer (NSCLC), molecular testing for certain mutations is crucial in daily clinical practice and is recommended by international guidelines. To date, a standardized approach to identify druggable genetic alterations are lacking. We have developed and implemented a new diagnostic algorithm to harmonize the molecular testing of NSCLC. Patients and methodsIn this retrospective analysis, we reviewed 119 patients diagnosed with NSCLC at the University Hospital Zurich. Tumor samples were analyzed using our standardized diagnostic algorithm: After the histological diagnosis was made, tissue samples were further analyzed by immunohistochemical stainings as well as the real-time PCR test Idylla™. Extracted DNA was further utilized for comprehensive genomic profiling (FoundationOne®CDx, F1CDx). ResultsOut of the 119 patients were included in this study, 100 patients were diagnosed with non-squamous NSCLC (nsqNSCLC) and 19 with squamous NSCLC (sqNSCLC). The samples from the nsqNSCLC patients underwent testing by Idylla™ and were evaluated by immunohistochemistry (IHC). F1CDx analysis was run on 67 samples and 46 potentially actionable genomic alterations were detected. Ten patients received the indicated targeted treatment. The median time to test results was 4 days for the Idylla test, 5 days for IHC and 13 days for the F1CDx. ConclusionIn patients with NSCLC, the implementation of a standardized molecular testing algorithm provided information on predictive markers for NSCLC within a few working days. The implementation of broader genomic profiling led to the identification of actionable targets, which would otherwise not have been discovered.

Cemiplimab + Chemo Shows Clinical Benefit in Advanced NSCLC

Cemiplimab + Chemo Shows Clinical Benefit in Advanced NSCLC

Updated Findings of the Phase II LCMC3 Trial of Lung Cancer Patients

Lung Cancer: Lung CancerResults from an exploratory analysis of the Phase II LCMC3 trial showed that patients with resectable Stage IB-IIIB non-small cell lung cancer (NSCLC) who received adjuvant atezolizumab following neoadjuvant atezolizumab and resection had improved disease-free survival compared with those who were not administered adjuvant atezolizumab. These findings, presented during the 2023 European Lung Cancer Congress, also demonstrated a trend toward improved overall survival among patients who underwent adjuvant atezolizumab (Abstract 145MO). “Neoadjuvant chemoimmunotherapy (IO) treatment without adjuvant treatment in CheckMate 816 has shown to improve pathologic responses and event-free survival outcomes,” noted study author David P. Carbone, MD, PhD, the Barbara J. Bonner Chair in Lung Cancer Research and Director of the James Thoracic Center at The James Ohio State University Comprehensive Cancer Center. “However, it is completely unclear what the role of adjuvant immunotherapy is after neoadjuvant immunotherapy and there is no current study testing the role of adjuvant IO.” LCMC3 (NCT02927301) is an open-label, single-arm, Phase II study of neoadjuvant followed by optional adjuvant atezolizumab (anti-PD-L1) in resectable NSCLC. The primary endpoint—major pathological response (MPR)—was met with an observed MPR rate of 20 percent after neoadjuvant atezolizumab in patients without EGFR or ALK alterations who underwent surgery (Nature Med 2022; doi: 10.1038/s41591-022-01962-5). Carbone and colleagues report updated disease-free survival, overall survival, and safety data from patients who received adjuvant atezolizumab versus those who did not. Methods & Findings Patients eligible for this study included those 18 years or older who had Stage IB-IIIA or select IIIB NSCLC, as well as an ECOG performance status of 0-1. The primary endpoint was major pathologic response (≤10% viable tumor cells). Secondary endpoints included pathologic response by PD-L1 and radiographic response by PD-L1, TMB, neoantigen, and GEP. Disease-free survival, overall survival, and biomarkers were exploratory endpoints. Safety was also examined during the adjuvant phase. Study participants received neoadjuvant atezolizumab (1,200 mg IV for ≤2 cycles) followed by surgery. Individuals without disease progression had the option to undergo adjuvant atezolizumab every 3 weeks for ≤12 months. With a data cutoff of October 21, 2022, the primary efficacy population included 137 patients without EGFR/ALK alterations who had surgery and MPR assessment. Of those, 53 (39%) received adjuvant atezolizumab and 84 (61%) did not. The baseline characteristics between these two groups were generally well-balanced, according to Carbone. However, he did note that patients who received adjuvant atezolizumab had a higher rate of squamous NSCLC (47% vs. 31%). They were also more likely to have a PD-L1 tumor proportion score (TPS) of 50 percent or higher (40% vs. 27%) and MPR status (42% vs. 8%) when compared to their counterparts who did not receive adjuvant atezolizumab. Study authors reported an updated 3-year disease-free survival and overall survival rate for the entire cohort of 72 percent and 82 percent, respectively. Disease-free and overall survival rates for Stage I/II were 75 percent and 82 percent, and 68 percent and 81 percent for Stage III. In the MPR-evaluable population, the 3-year disease-free survival rate was 83 percent for those who were given adjuvant atezolizumab versus 64 percent for those who did not receive this treatment. Among patients without MPR (n=108), Carbone reported a 3-year disease-free survival of 80 percent for individuals who underwent adjuvant atezolizumab compared with 62 percent for those who did not. Three-year overall survival was 87 percent and 75 percent, respectively. Carbone reported no unexpected safety findings. Among patients in the adjuvant atezolizumab safety population (n=57), any-grade adverse events (AEs) were observed in 96 percent of patients, including Grade 3/4 (40%) and Grade 5 (5%) adverse events. Treatment-related adverse events of any grade were reported in 63 percent of patients. Twenty-one percent had a Grade 3 treatment-related adverse event. Study authors reported that 23 percent of patients experienced any-grade AEs that led to treatment discontinuation, including 19 percent with Grade 3/4 (19%) and Grade 5 (2%) adverse events. Immune-mediated adverse events were seen in 46 percent of patients treated with adjuvant atezolizumab. This included 16 percent with a Grade 3/4 event. Study authors reported that 33 percent of patients experienced any-grade immune-mediated treatment-related adverse events with 16 percent being Grade 3/4. Significance & Implications This exploratory analysis suggests that LCMC3 patients with resectable NSCLC who received adjuvant atezolizumab may have improved disease-free survival and showed a trend toward improved overall survival when compared with those who did not receive adjuvant atezolizumab, according to Carbone. “The non-MPR subgroup also showed a trend toward improved disease-free survival and overall survival in patients who received adjuvant atezolizumab,” he said, while also emphasizing that adjuvant atezolizumab was well-tolerated with no new safety concerns. “This single-arm study showed that outcomes were better than anticipated in patients who received adjuvant atezolizumab, which may prompt further studies of IO monotherapy,” Carbone concluded. Catlin Nalley is a contributing writer.

Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC.

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC.

PD-L1 expression as a unique negative predictive biomarker in advanced squamous NSCLC when treated with first-line chemotherapy.

e21140 Background: PD-L1 expression has been established as a positive predictive biomarker for immune checkpoint inhibition in advanced non-small cell lung cancer (NSCLC). We hypothesize that PD-L1 serves as a negative predictive biomarker of chemotherapy in squamous NSCLC in contrast to non-squamous NSCLC. Methods: Phase III randomized trials that investigated PD-L1 expression as a biomarker in advanced squamous NSCLC at first-line were identified and included through a systematic search of Embase and PubMed from inception until 24th September, 2022. To investigate the anti-thesis, trials that reported PD-L1 stratified KM plots in non-squamous NSCLC were evaluated too. Only trials that reported PD-L1 stratified KM curves of chemotherapy arms were included. A graphical reconstructive algorithm was used to retrieve survival data from reported Kaplan-Meier (KM) curves. Pooled survival analyses for progression-free and overall survival (PFS, OS) were conducted with Cox proportional hazard models with a shared-frailty term incorporated to account for inter-study differences. Results: Five phase III randomized trials (2 squamous NSCLC and 3 non-squamous NSCLC) reporting PD-L1 stratified KM plots of patients treated with first-line chemotherapy were included. In patients with squamous histology, PD-L1 expression negatively predicted for chemotherapy benefit – patients with higher PD-L1 expression were at a higher risk of tumour progression (PD-L1 ≥50% [n = 187] vs PD-L1 &lt; 1% [n = 247]: HR = 1.474, 95%-CI: 1.171-1.855, p &lt; 0.001; PD-L1 ≥50% [n = 187] vs PD-L1 1-49% [n = 239]: HR = 1.300, 95%-CI: 1.033-1.625, p = 0.025). Conversely, in patients with non-squamous histology, no significant differences in tumour progression was shown between PD-L1 subgroups (PD-L1 ≥50% [n = 137] vs PD-L1 &lt; 1% [n = 242]: HR = 1.238, 95%-CI: 0.919-1.667, p = 0.160; PD-L1 ≥50% [n = 137] vs PD-L1 1-49% [n = 199]: HR = 0.958, 95%-CI: 0.714 -1.285, p = 0.780). No significant difference in OS was found between PD-L1 subgroups dichotomized at 1% &amp; 50% among patients with squamous histology. In contrast, in patients with non-squamous histology, PD-L1 was a positive biomarker for chemotherapy benefit – patients with higher PD-L1 were at a lower risk of mortality (PD-L1 ≥50% [n = 40] vs PD-L1 &lt; 1% [n = 150]: HR = 0.523, 95%-CI: 0.316-0.865, p = 0.012). Conclusions: These findings suggest that PD-L1 expression is uniquely a negative predictor for tumour progression in advanced squamous NSCLC treated with first-line chemotherapy.

Phase 2 clinical trial of the proautophagic drug ABTL0812 combined with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung carcinoma.

9059 Background: ABTL0812 induces the inhibition of Akt/mTOR pathway by upregulation of TRIB3 protein, an endogenous Akt inhibitor, and promotes endoplasmic reticulum (ER) stress. As a result, ABTL0812 induces cytotoxic autophagy that leads to specific death of cancer cells, without affecting non-tumor cell viability. A Phase II clinical trial was designed where ABTL0812 was evaluated in combination with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung cancer (NSCLC). Methods: ABTL0812 was administered 1300 mg TID orally with 175 mg/m2 paclitaxel and AUC5 carboplatin every 3 weeks, for up to 8 cycles, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients with non-irradiable IIIb stage or stage IV squamous NSCLC. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety and tolerability according to CTCAE v4.03, pharmacokinetics (PK) of ABTL0812 enantiomers ((-)-ABTL and (+)-ABTL) and pharmacodynamics assessed by two surrogate blood biomarkers: TRIB3 and CHOP. Results: Forty patients were included; median age was 66.1 years old; 90% men/10% women; 100% ECOG 0-1; 30% current smokers/67.5% former smokers and 37.5% had received prior chemotherapy &gt; 12 months before inclusion. 39 patients had at least 1 adverse event (AE), anemia appeared in 32.5% of the patients (5.0% grade 3), neutropenia in 27.5% (25% grades 3-4) and thrombocytopenia in 17.5% of the patients (2.5% grade 3). For non-hematological AEs, asthenia was reported in 62.5% of the patients (2.5% grade 3); diarrhea in 45% (no grade 3-4) and nausea in 37.5% (5% grades 3-4). Twenty-five patients reach the primary endpoint for efficacy evaluation. ORR was 52.0% (95% CI 34.2-65.9) and 32.0% of the patients had stable disease. Median OS was 22.5 months (10.4-NC), median progression free survival 6.2 months (4.4-8.8), and DOR 5.1 months (3.9-7.4). Area under the curve (µg·h/ml) for (-)-ABTL and (+)-ABTL were 39.0±12.3 and 17.1±6.3 respectively, maximal concentrations (µg/ml) were 6.4±2.6 and 5.1±2.2 and minimum concentrations (µg/ml) 2.2±1.5 and 0.8±1.3. TRIB3 and CHOP PD biomarkers were induced by the treatment. Conclusions: The combination of ABTL0812 with paclitaxel and carboplatin shows survival outcomes that compare favorably with historical controls in squamous-NSCLC with an acceptable safety profile. PK analysis is compatible with drug activity, and pharmacodynamic analysis shows drug engagement. Clinical trial information: NCT03366480 .

LUNG-IST-127: A pilot phase II study of maintenance cabozantinib plus pembrolizumab for patients with metastatic squamous non-small cell lung cancer (sqNSCLC) with disease control following induction therapy.

TPS9151 Background: First-line combination chemotherapy with pembrolizumab followed by maintenance pembrolizumab is the standard of care treatment for patients with metastatic sqNSCLC. This was established by the phase III KEYNOTE-407 trial, which demonstrated a median progression-free survival (PFS) of 6.4 months in the experimental arm. Despite these advances, there remains a need to continue to improve upon survival outcomes for these patients. Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinsases including MET, VEGFRs, AXL, RET, and ROS, which are receptors involved in tumor cell-proliferation, angiogenesis, and immune cell regulation. Preclinical studies have demonstrated the ability of cabozantinib to modulate both adaptive and innate immune cells and to exhibit synergistic activity when used in combination with immune checkpoint inhibitors. We hypothesize that cabozantinib in combination with pembrolizumab in the maintenance phase of first-line treatment of metastatic sqNSCLC will prolong median PFS with a tolerable toxicity profile. Methods: LUNG-IST 127 is a pilot phase II, single-arm clinical trial of maintenance cabozantinib in combination with pembrolizumab for patients with metastatic sqNSCLC who achieved disease control following standard 1L induction therapy with chemotherapy and pembrolizumab. Thirty-six patients will be enrolled at 2 US sites to receive first-line induction therapy with carboplatin, nab-paclitaxel or paclitaxel, and pembrolizumab for four cycles. After induction therapy, those who have achieved disease control based on re-staging imaging will continue onto maintenance therapy with cabozantinib 40mg PO daily in combination with pembrolizumab 200mg IV every 3 weeks. The primary endpoint is PFS estimated by Kaplan-Meier methods with associated 95% confidence intervals. Based on an exploratory power analysis using an elevated one-sided alpha level of 0.40, we hypothesize that the proposed therapy will prolong median PFS from 6.4 to 9 months. Key secondary endpoints include overall survival (OS), overall response rate (ORR), and characterizing the safety and tolerability of cabozantinib in combination with pembrolizumab. Quality of life will also be measured with the EORTC QLQ-C30. Correlative endpoints include characterizing cfDNA from biofluids and assessing the change in circulating immune cells in different phases of treatment in association with PFS and OS. This trial would be the first to address whether there is clinical benefit in utilizing combination cabozantinib and pembrolizumab in the maintenance phase of treatment in metastatic sqNSCLC. Clinical trial information: NCT05613413 .

EGRET: A first-in-human study of the novel antibody-drug conjugate (ADC) AZD9592 as monotherapy or combined with other anticancer agents in patients (pts) with advanced solid tumors.

TPS3156 Background: The epidermal growth factor receptor (EGFR) and mesenchymal-epidermal transition tyrosine kinase receptor (c-MET) are expressed in diverse solid tumors, and function as driver genes in some types. Clinical benefit of bispecific monoclonal antibodies (Ab) targeting these receptors was demonstrated in pts with EGFR mutated (EGFRm) non-small-cell lung cancer (NSCLC), but an ADC targeting these receptors has not been developed. AZD9592 is an ADC with a bispecific Ab targeting EGFR and c-MET. When internalized, AZD9592 releases a topoisomerase 1 inhibitor (TOP1i) warhead that traps TOP1 on DNA, causing double-strand breaks and induction of apoptotic cell death. Preclinical data have demonstrated promising efficacy and safety of AZD9592 in tumors expressing EGFR and c-MET, including but not limited to adenocarcinoma and squamous NSCLC and head and neck squamous cell carcinoma (HNSCC). Methods: EGRET is a phase 1, open-label, multicenter, modular study in pts with advanced solid tumors (NCT05647122). Module 1 will evaluate AZD9592 monotherapy in pts with metastatic NSCLC (mNSCLC) with EGFRm (sensitizing L858R mutation or exon 19 deletions) or EGFR wild-type, or recurrent or metastatic HNSCC. Module 2 will evaluate AZD9592 in combination with osimertinib in pts with EGFRm mNSCLC. Each module will include dose escalation (Part A) and dose expansion (Part B) cohorts. Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, life expectancy ≥12 weeks, measurable disease per RECIST v1.1, and adequate organ and bone marrow function. Key exclusion criteria for both modules include unresolved toxicities of Grade ≥2 (NCI CTCAE v5.0) from prior therapy, uncontrolled intercurrent illness, cardiovascular disorders, history of drug-induced interstitial lung disease or pneumonitis, and previous treatment with a TOP1i ADC or an EGFR- or MET-targeted ADC. Treatment continues until disease progression, initiation of alternative anticancer therapy or unacceptable toxicity. The primary objectives of Part A are to assess safety and tolerability, and to determine the maximum tolerated dose and/or the recommended phase 2 dose of AZD9592 as monotherapy or in combination with osimertinib. The primary objectives for Part B are to evaluate safety and tolerability, and antitumor activity by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary objectives for both Part A and B include assessing AZD9592, as monotherapy and in combination with osimertinib, for efficacy (by ORR, disease control rate, duration of response, and progression-free and overall survival), pharmacokinetics, and immunogenicity. Descriptive statistics will be used for all variables. The study will include sites across the EU, USA, and Asia Pacific; sites in USA and Australia are currently open for enrollment. Clinical trial information: NCT05647122 .

ARC-10: A phase 3 study to evaluate zimberelimab + domvanalimab versus pembrolizumab in front-line, PD-L1-high, locally advanced or metastatic non–small-cell lung cancer.

TPS9148 Background: Despite improvements in the management of locally advanced or metastatic non–small cell lung cancer (NSCLC) from programmed cell death/ligand protein 1 (PD-[L]1) inhibition, there remains an unmet need for improved treatment options. PD-L1 expression is a known biomarker of response to anti–PD-L1 therapies in metastatic NSCLC. The combination of PD-1 inhibition with inhibition of the immunosuppressive T cell Immunoglobulin and ITIM domain (TIGIT) pathway is associated with improved response and prolonged progression-free survival in patients with advanced NSCLC. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks TIGIT, thereby reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) is an mAb that binds to PD-1 on T/NK cells, preventing PD-L1-mediated immunosuppressive effects and resulting in tumor cell death. This phase 3 study will investigate the efficacy and safety of combination therapy with dom + zim compared with pembrolizumab monotherapy in patients with PD-L1-high NSCLC. Methods: ARC-10 (NCT04736173) is a global, phase 3, randomized, multicenter, open-label study. Eligible patients are adults with histologically confirmed, treatment-naive, locally advanced or metastatic, squamous or non-squamous NSCLC with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, high expression of PD-L1 (tumor cells [TC] ≥50%), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients must not have genomic tumor aberrations for which targeted therapies are approved and available (eg, EGFR, ALK, ROS, BRAF, NTRK). Approximately 600 patients will be randomized 1:1 to receive combination therapy with dom + zim (dom 1200 mg intravenous [IV] once every 3 weeks [Q3W] + zim 360 mg IV Q3W) or pembrolizumab monotherapy (200 mg IV Q3W) for 21-day cycles until disease progression, intolerance, or a maximum of 35 cycles. Randomization will be stratified by ECOG performance status (0 vs 1), geographical region (Asia vs non-Asia), and histology (squamous vs non-squamous). The primary efficacy endpoint is overall survival. Secondary efficacy endpoints include blinded independent central review of progression-free survival and confirmed overall response rate according to RECIST v1.1. Safety endpoints include the presence of treatment-emergent adverse events and laboratory parameters. Health-related quality of life will be assessed by measuring the time to first symptom deterioration in the NSCLC-Symptom Assessment Questionnaire total score. Study recruitment is planned in Asia, North and South America, Africa, and Europe. Clinical trial information: NCT04736173 .

Phase II results of ivonescimab (AK112/ SMT112), a novel PD-1/VEGF bispecific, in combination with chemotherapy for first line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) in EGFR/ALK.

9087 Background: Since the initial approval of bevacizumab (bev) with chemo in NSCLC, the subsequent focus of bev use in combination with PD1 therapy for first line metastatic disease has largely focused on non-squamous (non-SCC) histology. Ivonescimab is a novel anti-PD-1/VEGF bispecific antibody. The bispecific approach to these targets has the potential to recalibrate the malignant immuno-architecture in favor of a more immune-responsive and anti-tumor microenvironment. Cooperative VEGF binding with the bispecific has been shown to elevate affinity of ivonescimab to PD-1 by more than 10-fold. Ivonescimab has a mean T1/2 of 6-7 days while bev T1/2 is 20 days. Therefore, we aimed to assess the efficacy and safety of ivonescimab combined with chemotherapy for first line advanced or metastatic NSCLC in patients (pts) with squamous (SCC) or non-SCC NSCLC. Methods: An open-label, multi-center phase II study evaluating the efficacy and safety of ivonescimab combined with chemotherapy in pts with advanced or metastatic NSCLC. Pts were enrolled into 3 cohorts based on prior therapy and presence of AGA. Data from pts with prior therapy for advanced or metastatic disease were presented in ASCO 2022 and here we report additional pts and longer-term data from pts with NSCLC without AGA receiving first line therapy for advanced/metastatic disease. Pts were treated with 10 or 20 mg/kg ivonescimab once every 3wks combined with carboplatin and pemetrexed (non-SCC) or carboplatin and paclitaxel (SCC). The primary endpoint was ORR per RECIST by investigator. Results: 135 pts with advanced or metastatic NSCLC received ivonescimab plus chemotherapy including 63 with SCC and 72 with non-SCC. Median age was 61 yrs (. 78% male, 3% and 97% pts had ECOG PS 0 and 1, respectively, and 20% pts had baseline brain metastasis. Median follow-up was 11.5 mo. Pts with SCC experienced a 75% ORR with median DOR 15.4 mo, 95% DCR, the 9-mo PFS and OS rate was 67% and 93%, respectively. Pts with non-SCC experienced a 55% ORR, DOR was not reached, 100% DCR, the 9-mo PFS rate and OS rate was 61% and 81%, respectively. The most common treatment related adverse events (TRAEs)≥ 10% were epistaxis, proteinuria, rash, amylase increased, anemia, ALT increased, infusion related reaction, AST increased, pruritus, decreased appetite, and WBC decreased. Grade ≥3 TRAEs occurred in 28.1% TRAE leading to discontinuation occurred in 6.7% of pts. Conclusions: Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely in combination with platinum doublet chemotherapy to patients with SCC and non-SCC histology. Clinical trial information: NCT04736823 .

Clinical benefit of pembrolizumab in treatment of first line non-small cell lung cancer: a systematic review and meta-analysis of clinical characteristics

ObjectivePembrolizumab has become an integral first line therapeutic agent for non-small cell lung cancer (NSCLC), but its potential predictive role in clinical and molecular characteristics remains to be clarified. Accordingly, we performed a systematic review and meta-analysis to evaluate the clinical benefit of pembrolizumab in treatment of first line NSCLC and to select individuals with the greatest potential benefit from pembrolizumab therapy, in order to obtain a more accurate treatment of NSCLC in immunotherapy.MethodsMainstream oncology datasets and conferences were searched for randomized clinical trials (RCTs) published before August 2022. RCTs involved individuals with first line NSCLC treated with pembrolizumab monotherapy or in combination with chemotherapy. Two authors independently selected the studies, extracted data, and assessed the risk of bias. The basic characteristics of the included studies were recorded, along with 95 percent confidence intervals (CI) and hazard ratios (HR) for all patients and subgroups. The primary endpoint was overall survival (OS), and secondary endpoints was progression-free survival (PFS). Pooled treatment data were estimated using the inverse variance-weighted method.ResultsFive RCTs involving 2,877 individuals were included in the study. Pembrolizumab-based therapy significantly improved OS (HR 0.66; CI 95%, 0.55–0.79; p < 0.00001) and PFS (HR 0.60; CI 95%, 0.40–0.91; p = 0.02) compared with chemotherapy. OS was substantially enhanced in individuals aged < 65 years (HR 0.59; CI 95%, 0.42–0.82; p = 0.002), males (HR 0.74; CI 95%, 0.65–0.83; p < 0.00001), with a smoking history (HR 0.65; CI 95%, 0.52–0.82; p = 0.0003), with PD-L1 tumor proportion score (TPS) < 1% (HR 0.55; CI 95%, 0.41–0.73; p < 0.0001) and TPS ≥ 50% (HR 0.66; CI 95%, 0.56–0.76; p < 0.00001), but not in individuals aged ≥ 75 years (HR 0.82; CI 95%, 0.56–1.21; p = 0.32), females (HR 0.57; CI 95%, 0.31–1.06; p = 0.08), never smokers (HR 0.57; CI 95%, 0.18–1.80; p = 0.34), or with TPS 1–49% (HR 0.72; CI 95%, 0.52–1.01; p = 0.06). Pembrolizumab significantly prolonged OS in NSCLC patients, regardless of histology type (squamous or non-squamous NSCLC), performance status (PS) (0 or 1), and brain metastatic status (all p < 0.05). Subgroup analysis revealed that pembrolizumab combined with chemotherapy had more favorable HR values than pembrolizumab monotherapy in improving the OS of individuals with different clinical and molecular features.ConclusionPembrolizumab-based therapy is a valuable option for first line treating advanced or metastatic NSCLC. Age, sex, smoking history and PD-L1 expression status can be used to predict the clinical benefit of pembrolizumab. Cautiousness was needed when using pembrolizumab in NSCLC patients aged ≥ 75 years, females, never smokers, or in patients with TPS 1–49%. Furthermore, pembrolizumab in combination with chemotherapy may be a more effective treatment regimen.

Cost-effectiveness analysis of toripalimab plus chemotherapy as the first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) without EGFR or ALK driver mutations from the Chinese perspective.

Objectives: The results of a CHOICE-1 study demonstrated the superior efficacy of toripalimab (anti-PD-1 antibody) plus chemotherapy for patients with advanced non-small cell lung cancer (NSCLC), with a manageable safety profile. This study was performed to evaluate the economic value of this treatment for this patient population from the Chinese payer's perspective. Materials and methods: Basic data were derived from the CHOICE-1 study. Markov models were developed to simulate the process of advanced NSCLC, including the progression-free survival (PFS), progressive disease (PD), and death in intention-to-treat (ITT) populations, as well as patients with squamous or non-squamous NSCLC. The cost was obtained from the local institution, and the value of utilities referred to previous studies. Monte Carlo simulations were performed to depict the probabilistic scatter plots of the incremental cost-effectiveness ratio (ICER) and acceptability curves, aiming to address the uncertainty of model inputs. Results: Compared with standard chemotherapy, toripalimab plus chemotherapy yields an ICER of $21,563 per quality-adjusted life year (QALY) in the ITT population. For patients with squamous NSCLC, comparing the combined therapy with chemotherapy led to an ICER of $18,369 per QALY, while the ICER was $24,754 per QALY in patients with non-squamous NSCLC. With the threshold of willingness to pay we set ($37,653 per QALY), toripalimab plus chemotherapy was cost-effective in these patient populations. Conclusion: For patients with advanced NSCLC, toripalimab plus chemotherapy was an optimal choice as first-line treatment, regardless of histology.

Abstract CT199: Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade

Abstract Type-2 cytokines are hypothesized to promote an immune-permissive milieu for cancer to grow. Through scRNAseq and CITEseq on human non-small cell lung cancer (NSCLC) and the krasG12Dp53−/− lung cancer model we previously described a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the “mregDC,” that was also notable for a strong Th2 immune signature. We subsequently blocked the canonical Th2 cytokine IL-4 in vivo in tumor-bearing mice, and found that this significantly decreased lung tumor burden, which was recapitulated in multiple other tumor models. Furthermore, this effect synergized with PD-L1 blockade. Based on this data, we designed a clinical trial to assess if the addition of dupilumab, an anti-IL-4Ra antibody widely used for treatment of atopic diseases, may rescue responses to checkpoint blockade (NCT05013450). In this Phase 1b/2 trial, up to 21 patients with NSCLC that have progressed on prior anti-PD-(L)1 therapy will be enrolled. Patients continue PD-(L)1 blockade while receiving three doses of dupilumab, administered every three weeks, with initial radiographic assessment of response at 9 weeks. Patients without progression of disease then continue anti-PD-(L)1 alone. The primary endpoint of Phase 1b is safety and tolerability, while the primary endpoint of Phase 2, inclusive of patients from Phase 1b, is efficacy as per RECIST. Patients undergo pre- and on-treatment biopsies, pre-treatment stool collection for microbiome analysis, as well as blood collection at 6 timepoints for PBMCs, plasma and ctDNA. Here we report the Phase 1b portion that has completed accrual in which 6 patients were enrolled in a Phase 1b run-in to confirm safety and tolerability. There were no adverse events attributable to study treatment during Phase 1b in any of the 6 patients treated. Serum proteomic analysis of this cohort revealed that dupilumab treatment induced a profound increase in proinflammatory/tumoricidal immune effector molecules, and reversed a systemic Th2 cytokine signature. Furthermore, mass cytometry of circulating immune populations showed an expansion of cytotoxic lymphocyte populations and a reduction in immunosuppressive myeloid cells. The fourth patient treated on trial who had progressive disease after 9 cycles of consolidation checkpoint blockade following concurrent chemoradiation for squamous NSCLC was enrolled, and had a partial response at 9 weeks, with deepening of the PR at 25 weeks. This patient’s on-treatment biopsy showed a major increase in CD8 T cell tumor infiltration. Histological analysis using spatial transcriptomics and multiplexed imaging from these patients is ongoing, and will be reported at the conference. Based on this promising signal in the initial lead-in, the trial will proceed through Simon’s Two Stage design and enroll a full 21 patients as part of the Phase 2 expansion cohort. This clinical trial is funded entirely through philanthropy support through the Tisch Cancer Institute. Citation Format: Thomas Urban Marron, Nelson M. LaMarche, Matthew D. Park, Samarth Hegde, Bailey Fitzgerald, Clotilde Hennequin, Raphael Mattiuz, Meriem Belabed, Jessica Le Berichel, Barbara Maier, Nicole Hall, Justin Miller, Deborah B. Doroshow, Nicholas Rohs, Rajwanth Veluswamy, Nicholas Venturini, Jorge E. Gomez, Christian Rolfo, David Yankelevitz, Udit Chaddha, Timothy Harkin, Mary B. Beasley, Seunghee Kim-schulze, Sacha Gnjatic, Fred R. Hirsch, Miriam Merad. Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT199.

Abstract 281: Phosphodiesterase 8/9 inhibition to sensitize squamous non-small cell lung cancer (NSCLC) to pemetrexed (PMX): A double-edge strategy

Abstract Introduction. Phosphosidesterases (PDE) are key regulators of cyclic nucleotide (cAMP/cGMP) signaling regulating many cellular processes including cell proliferation, growth arrest and apoptosis. In squamous NSCLC (SCC), PDE inhibitors (PDEi) have shown anti-tumor activity both as single agent and in combination with chemotherapy. A strong putative synergistic mechanistic activity exists between pemetrexed (PMX) and PDEi through cAMP/Protein kinase A (PKA) and cGMP/Protein Kinase G signaling. We therefore thought to investigate whether SCC, classically resistance to PMX can be sensitized to the drug through PDE inhibition. Methods. Whole exome sequencing and survival data from TCGA was surveyed to identify PDEs most closely associated with clinical outcome in NSCLC. Whole exome sequencing data from GEmiCCL database were used to select SCC cell lines with unaltered PDE genes. Two SCC cell lines (H226, H1703) were evaluated for viability (WST8 assay), proliferation and apoptosis (Apo-Tox-Glo assay) after treatment with PMX with or without sildenafil citrate, PF-04671536 or PF-04447943 (PDE5i, PDE8i and PDE9i respectively). PDE expression was quantified by qPCR and Western Blot (WB). PDE activity and downstream signaling was quantified by measuring PKA/PKG target activation (PKA/pVASP157, PKG/pVAP239). Results. Presence of function altering mutations in PDE8 (cAMP/PKA signaling) and PDE9 (cGMP/PKG signaling) improved NSCLC overall survival (P&amp;lt;0.1). PDE5 (cGMP/PKG signaling) mutations had no significant clinical impact. Both SCC cell lines investigated expressed high level of PDE8-9, but H1703 had only trace levels of PDE5. Endogenous PKA activity and PKG activity was significantly lower in H1703 cells compared with H226. PDEi stimulated SCC cell growth (30-60% increase). PDE8i and PDE9i (EC50&amp;lt;40nM, significant PKA/PKG activation) were more potent than PDE5i (&amp;gt;1.5µM, no PKA/PKG activation). PMX also displayed a pro-mitotic activity toward SCC (40% increase at 250µM) coupled with significant PKA activation in H226 and PKG activation in H1703 cells. Combination of PDE5i, 8i or 9i (2X EC50 concentrations) with low dose PMX (0.025µM) inhibited SCC cell growth, H1703 showing greater response than H226 (30-37% vs 8-11% growth reduction). No cell death, necrosis or apoptosis, was detected. This cytostatic activity of PDEi combination treatment was not observed at high dose PMX (250µM). Conclusions. In the absence of PDE mutations, single agent PDE5i, 8i and 9i promote SCC growth with PDE8,9i displaying a far greater potency than PDE5i. PMX is also pro-mitotic toward SCC cells but PDE5i, 8i, and PDE9i can sensitize SCC cells to the drug. SCC cells with lower endogenous PKA/PKG activity are more sensitive to PDEi+PMX treatment. This combination is not cytotoxic though, rather is cytostatic, and displays a very narrow window of therapeutic activity. Citation Format: Anna V. Ivanina Foureau, David M. Foureau, Carol J. Farhangfar, Kathryn F. Mileham. Phosphodiesterase 8/9 inhibition to sensitize squamous non-small cell lung cancer (NSCLC) to pemetrexed (PMX): A double-edge strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 281.

Abstract 1888: IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer

Abstract Exhaustion of immune cells in the tumor microenvironment has been found and confirmed in many tumor cases, accounting for the major problems of current PD1/L1-oriented immunotherapy. There are two types of exhausted T cells present in the tumor microenvironment: progenitor exhausted T cells and terminally exhausted T cells. Data from various mouse syngeneic tumor models suggest that the dominance of progenitor exhausted T cells will be replaced by terminally exhausted T cells as the tumor progresses. The PD1/PDL1 antibodies mainly act on progenitor exhausted T cells and can develop acquired resistance as terminally exhausted T cells become the dominant cells in the tumor microenvironment. Recently, there are studies demonstrating that IL10 can restore the oxidative phosphorylation metabolism of terminally exhausted T cells and restore their potent killing activities of tumor cells. We therefore designed IAE0972, a novel EGFR/IL10 immunocytokine to solve the problems of immune cell exhaustion in current immunotherapy. It is a monovalent anti-EGFR antibody fused with IL10 homodimer. The anti-EGFR antibody can specifically enrich IAE0972 in tumor microenvironment, so that IL10 can reinvigorate antigen specific CD8+ T cells and facilitate its proliferation, while preserving the tumor cell proliferation inhibition activities of EGFR antibody. The design of monovalent form anti-EGFR antibody can also avoid the skin toxicity problem. In this study, we studied the target binding activity, CD8+ T cell activation activity and cancer cell proliferation inhibition activity of IAE0972. We also observed a much higher anti-tumor efficacy of IAE0972 in a MC38 syngeneic tumor model compared with that of Cetuximab. In addition, the molecule has a very good safety profile with MTD over 6 mg/kg and no skin toxicities, which is about 300-fold higher than that of cytokine drugs. In summary, IAE0972 is an innovative EGFR/IL10 immunocytokine with robust preclinical anti-tumor efficacy and favorable safety profile, which has the potential to address acquired resistance of current immunotherapy. IAE0972 is the first EGFR/IL10 immunocytokine with IND approval from both FDA and NMPA. The indications of IAE0972 include colorectal cancer, head and neck squamous cell carcinoma, squamous non-small cell lung cancer, and other EGFR positive tumors. A Phase I/IIa clinical trial to evaluate the safety, tolerability and preliminary efficacy of IAE0972 in patients with locally advanced or metastatic malignant tumors is on-going (NCT05396339). Citation Format: Liusong Yin, Xiaoling Jiang, Chongbing Wu, Zi Chen. IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1888.