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Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)

Purpose: Patients with advanced non–small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype. Experimental Design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens. Results: We identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell–mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells. Conclusions: These data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations.

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.

IL-6 modulates expression of NK receptor and their ligands in EGFR mutant tumors.

Purpose:In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC.Patients and Methods:Patients with newly diagnosed stage II–IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes.Results:Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: −1.07–2.28). In each group, 6 patients (43%, 95% CI: 17.66–71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: −0.33–3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence.Conclusions:Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

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PURPOSE Local consolidative therapy (LCT) for patients with synchronous oligometastatic non–small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients. METHODS We identified all patients presenting between 2000 and 2017 with stage IV non–small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis. RESULTS Of 194 included patients, 121 received comprehensive LCT to all sites of disease with either surgery or radiation. TP53 mutations were identified in 40 of 78 (55%), KRAS in 32 of 95 (34%), EGFR in 24 of 109 (22%), and STK11 in nine of 77 (12%). At median follow-up of 96 months, median OS and PFS were 26 (95% CI, 23 to 31) months and 11 (95% CI, 9 to 13) months, respectively. On multivariable analysis, patients with EGFR mutations had lower mortality risk (hazard ratio [HR], 0.53; 95% CI, 0.29 to 0.98; P = .044) compared with wild-type patients, and patients with STK11 mutations had higher risk of progression or mortality (HR, 2.32; 95% CI, 1.12 to 4.79; P = .023) compared with wild-type patients. TP53 and KRAS mutations were not associated with OS or PFS. Among 71 patients with known EGFR mutational status who received comprehensive LCT, EGFR mutations were associated with lower mortality compared with wild-type (HR, 0.45; 95% CI, 0.22 to 0.94; P = .032). CONCLUSION When compared with wild-type patients, those with EGFR and STK11 mutations had longer OS and shorter PFS, respectively. EGFR mutations were associated with longer OS among oligometastatic patients treated with comprehensive LCT in addition to systemic therapy.

Background: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting. Methods: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (PFS) and overall survival (OS) were evaluated. Associations of clinical characteristics with outcomes were assessed using univariable and multi-covariate Cox Proportional Hazards regression models. Results: A total of 178 patients (median age = 63.3; 57.9% females) with a median follow-up time of 42.0 (Interquartile range: 22.9–67.8) months were enrolled. There was no significant difference in PFS between chemoIO vs. chemo groups (5.3 vs. 4.8 months, p = 0.8). Compared to the chemo group, patients who received withBev therapy trended towards better PFS (6.1 months vs. 4.8; p = 0.3; HR 0.79; 95% CI: 0.52–1.20), while patients treated with IO-mono had inferior PFS (2.2 months; p = 0.001; HR 2.22; 95% CI: 1.37–3.59). Furthermore, PD-L1 level was not associated with PFS benefit in the chemoIO group. Patients with EGFR-mutant LUAD with high PD-L1 (≥50%) had shorter PFS (5.8 months) than non-EGFR/ALK LUAD patients who received chemoIO (12.8 months, p = 0.002; HR 0.22; 95% CI: 0.08–0.56) as first-line treatment. Chemotherapy-based therapy rendered similar benefit to patients with either EGFR exon19 deletion vs. L858R in the LUAD. Conclusions: This retrospective analysis revealed that immunotherapy provided limited additional benefit to chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy alone or combined with bevacizumab remain good choices for patients with actionable EGFR mutations.

Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Actionable mutations refer to DNA alterations that, if detected, would be expected to affect patients’ response to treatments [...]

Background: Osimertinib, a 3rd-generation (gen) EGFR tyrosine kinase inhibitor (TKI), is standard of care in front-line (1L) patients with advanced EGFR mutant NSCLC; however, not all subgroups may benefit equally. In the phase 3 FLAURA study, patients with exon 19 deletions (ex19del) had a median progression-free survival (mPFS) of 21.4 months (mo); patients with L858R had a shorter mPFS of 14.4 mo. Poorer outcomes with L858R have also been reported with other 3rd-gen TKIs aumolertinib and lazertinib. These patients are a potential poor-risk subgroup for these therapies. Here, we explored outcomes of patients with L858R-driven NSCLC using real-world datasets (RWDs), analyzed potential contributors to poorer outcomes, including co-mutation incidence and osimertinib potency for each mutation, and report preclinical proof of concept of combination treatment BLU-945, an investigational next-gen L858R inhibitor, with osimertinib. Methods: Two large RWDs were analyzed for survival outcomes in 1L osimertinib-treated patients with ex19del or L858R from MD Anderson Cancer Center (MDACC; n=105) and the clinical-genomic Guardant INFORM database (EGFR ctDNA baseline positive; n=1386). IC50s of osimertinib on EGFR mutations and wildtype were determined in BaF3 cells. Preclinical studies of combination BLU-945 and osimertinib were performed in L858R-driven BaF3 xenograft models. Results: Both RWDs confirmed poorer prognosis for 1L osimertinib-treated patients with L858R vs ex19del. MDACC cohort showed a 12-mo PFS rate of 63% for L858R (n=45) vs 82% for ex19del (n=60); mPFS was immature. Guardant INFORM cohort (ctDNA baseline positive) had a median time-to-treatment discontinuation of 8 mo for L858R (n=517) and 11.4 mo for ex19del (n=869), P=0.003. Poor prognosis factors (including TP53 mutations and co-mutation number) were not significantly different between L858R and ex19del; both had a similar number of off-target mutations in post-osimertinib samples. Strong association was found between osimertinib cellular IC50 and osimertinib clinical trial outcomes (mPFS). Osimertinib exhibited most clinical and cellular activity on ex19del, followed by L858R, then G719X, and then exon 20 insertions. BLU-945 in combination with osimertinib in a BaF3 L858R xenograft model demonstrated a longer duration of response vs osimertinib monotherapy. Conclusions: In both RWDs, 1L osimertinib-treated patients with L858R-driven NSCLC had poorer outcomes vs ex19del, consistent with osimertinib’s weaker activity on L858R. Preclinically, BLU-945 in combination with osimertinib increased L858R inhibition, resulting in more durable antitumor activity in L858R xenografts vs osimertinib alone, supporting rationale for combination treatment in patients with L858R mutations. This combination is being evaluated in 1L patients with L858R in the SYMPHONY study (NCT04862780). Citation Format: Yasir Y. Elamin, Tyler Rouskin-Faust, Nicole Zhang, Teresa Green, Aditya Dhande, Brenton G. Mar, John V. Heymach, Chiara Conti. Poorer outcomes in EGFR L858R-driven NSCLC treated with osimertinib may be addressed with novel combination of BLU-945 and osimertinib [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 LB123.

Objectives: Small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas (NECs) share many clinical features, including limited response to immune checkpoint inhibitors (ICIs). However, preclinical data suggest synergistic response with combined ICI and poly (ADP-ribose) polymerase inhibitors (PARPi) in SCLC models. This single-institution, phase II trial (NCT04701307) assessed the efficacy of a combination of the anti-PD-1 monoclonal antibody, dostarlimab, with the selective PARPi, niraparib, in patients with relapsed SCLC or NECs. Methods: Eligible patients with SCLC (Cohort 1) or NECs (Cohort 2) had received at least one prior line of therapy and were treated with niraparib 300 mg (or 200 mg if Results: From Feb 2021 to Aug 2021, 14 and 9 patients enrolled with SCLC and NEC, respectively. NECs included tumors from gynecological, head/neck, and gastrointestinal sites. In Cohort 1 (SCLC), 12 of 14 patients were evaluable by RECISTv1.1, including 1 complete response (CR), while 4 patients not achieving partial response (PR) had minor responses (-2%, -14%, -19%, and -24% from baseline). Only 1 patient in this cohort achieved PFS6, though 2 additional patients progressed between 5 and 6 months. In Cohort 2 (NEC), 6 of 9 patients were evaluable by RECISTv1.1 and no CR/PRs were observed. One patient did experience durable minor response (-21%), but no patients achieved PFS6. Dose-limiting, niraparib-related hematological AEs, typically thrombocytopenia, occurred in 12 of 23 patients. Non-hematological, treatment-related serious AEs occurred in only 1 patient (Grade 3 inflammatory arthritis), while 1 additional patient experienced brief dose-interruption due to Grade 2 pneumonitis. Preliminary translational data, including bulk and single-cell RNAseq, indicate molecular features, such as transcriptional subtype, are shared across SCLC and NECs and may predict response to this combination. Conclusions: In heavily pre-treated patients across SCLC and NEC cohorts, combined niraparib and dostarlimab failed to exceed interim futility criteria. However, multiple SCLC patients experienced durable disease control, including one patient with sustained CR and associated translational studies point to potential biomarker-driven approaches in the future. Trial supported by GlaxoSmithKline. Citation Format: Carl M. Gay, C. Allison Stewart, Michael Frumovitz, Junya Fujimoto, Yuann xi, Qi Wang, Runsheng Wang, Veronica Novegil, Mehmet Altan, Tina Cascone, Arvind Dasari, Yasir Y. Elamin, Frank V. Fossella, Bonnie S. Glisson, Charles S. Lu, Marcelo V. Negrao, Ferdinandos Skoulidis, Natalie Vokes, Robert J. Cardnell, Ignacio I. Wistuba, Jing Wang, John V. Heymach, Lauren A. Byers. A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas [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 CT218.

Background: NRG1 fusions represent a rare and potentially actionable oncogenic alteration found in ~0.2% of solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks aberrant NRG1 fusion protein binding to HER3 thereby preventing ligand-dependent activation and dimerization resulting in complete inhibition of the PI3K/AKT and MAPK downstream signaling pathways. Seribantumab has shown significant anti-tumor activity in PDX models and in patients (pts) with solid tumors harboring NRG1 fusions. Methods: CRESTONE (NCT04383210) is a phase 2 study of seribantumab in adult pts with solid tumors harboring NRG1 fusions who received at least one prior therapy and were naïve to ERBB-targeted therapy (Cohort 1); pts previously treated with ERBB-targeted therapies (exploratory Cohort 2) and pts with tumors harboring additional molecular alterations (exploratory Cohort 3). Here, we present updated efficacy results for pts in Cohort 1 dosed at 3 g IV QW. Safety data are evaluated for pts enrolled in Cohort 1 and exploratory Cohorts 2 and 3. Results: As of Dec 2, 2022, 51 pts were enrolled across all cohorts with 30 pts in Cohort 1 dosed at 3 g IV QW. Median age was 62 years (range 19-84); median prior lines of therapy was 2 (range 1-7); tumor types included non-small cell lung cancer (NSCLC, n=30), pancreatic adenocarcinoma (PDAC, n=6), biliary tract/cholangiocarcinoma (CCA, n=6), breast (n=4), and others (n=5); 15 different NRG1 fusion partners were identified with CD74 (22%) and SLC3A2 (16%) as the most frequently reported. In the overall safety population, 41 pts (80%) reported at least one treatment-related adverse event (TRAE). The most common TRAEs (occurring in ≥20% of pts) were diarrhea (41%), fatigue (29%), rash (24%), and nausea (22%). Four pts (8%) experienced Gr 3/4 TRAEs; no Gr 5 TRAEs. The safety profile for Cohort 1 was similar to the overall safety population. Among the 30 pts in Cohort 1, 22 were evaluable for investigator assessed (INV) response per RECIST v1.1; 2 pts (9%) had confirmed complete response (CR), 6 pts (27%) had confirmed partial response (PR), and 13 pts (59%) had stable disease (SD) as their best overall response (BOR). The INV objective response rate (ORR, confirmed PR + CR) was 36% and disease control rate (DCR, confirmed PR+CR+SD) was 95%. The overall duration of response ranged from 1.4 to 17.2 months. In pts with NSCLC, the INV-ORR was 39% and DCR was 94%. Conclusions: Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option. Citation Format: Tejas Patil, Daniel R. Carrizosa, Mark E. Burkard, Karen L. Reckamp, Jayesh Desai, Young Kwang Chae, Stephen V. Liu, Kartik Konduri, Shirish M. Gadgeel, Jessica J. Lin, Parneet K. Cheema, David R. Spigel, Alison M. Schram, Valerie M. Jansen, Yasir Y. Elamin. CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors [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 CT229.

Background: Compared to other well-studied biomarkers, the relationship between overall tumor burden and immune-checkpoint inhibitor (ICI) efficacy is poorly understood. Methods: We identified patients with stage IV NSCLC without EGFR, ALK or ROS1 alterations treated on the LONESTAR protocol with nivolumab + ipilimumab with formal 3-month radiographic response evaluation. Response was annotated using RECIST 1.1. Manual segmentation of primary and measurable metastatic lesions on pre-treatment CT scans was performed, and tumor volume was calculated from these measurements. Tumor burden was defined as the involvement status, volume, or lesion counts within specific organs (lungs, pleura, lymph nodes, liver, adrenals, bone, and soft tissue) and across whole body. We explored the impact of baseline tumor burden on ICI response and its association with other clinical features. Results:152 patients were included; patients with progressive disease (PD; n=50) at 3 months were compared to all others (n=102). Overall disease volume correlated to tumor volume at the primary lesion (spearman rho=0.69), lymph node (rho=0.45), soft tissue (rho=0.23), lung metastases (rho=0.22), and pleura (rho=0.20); overall lesion counts correlated to lesion counts in lymph nodes (rho=0.61), lung metastases (rho=0.45), and bone (rho=0.16). On univariate analysis, overall tumor volume (P=2e-53) and lesion counts (P=2e-51) had the strongest association with PD, outperforming PD-L1 (P=0.02), ECOG performance status (PS, P=7e-16), and clinical variables including prior treatment and smoking status. PD correlated with higher disease burden in all individual organs except bone; adrenal metastases inversely correlated with PD. Volumetric features complemented PD-L1 and other clinical risk factors to predict PD; in a composite model (ClinVol) AUC=0.82, sensitivity=66%, specificity=93%, while PD-L1 alone yielded an AUC=0.62, sensitivity=94%, specificity=28%. Similar trends were observed for subgroup analyses stratified by brain metastasis status or smoking history, in which volumetric measures increased the power of PD-L1 to predict PD by a consistent AUC increase of ~0.2. Upon subgroup analysis stratified by PD-L1, volumetric models showed robust stratification of PD, with AUC of 0.97, 0.81, 0.81 respectively for PD-L1 Conclusion: Higher baseline tumor burden was associated with increased likelihood of disease progression on combination ICI therapy. ClinVol modeling improves predictive accuracy of 3-month progression. Citation Format: Muhammad Aminu, Natalie I. Vokes, Maliazurina B. Saad, Hui Li, Lingzhi Hong, Mohamed S. Mohamed, John Boom, Pingjun Chen, Mehmet Altan, Saumil Gandhi, Stephen Swisher, Mara B. Antonoff, Jenny V. Pozadzides, George Blumenschein Jr, Don L. Gibbons, Tina Cascone, Yasir Y. Elamin, Xiuning Le, Marcelo V. Negrao, Ferdinandos Skoulidis, Anne S. Tsao, Janet Tu, J.Jack Lee, Jianjun Zhang, John V. Heymach, Jia Wu. Tumor volumetric analysis to correlate disease burden with response to dual immune checkpoint blockade in metastatic NSCLC. [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 4393.

Background: Immune checkpoint inhibitors (ICIs) as monotherapy (ICI-mono) or with chemotherapy (ICI-chemo) are standard first-line treatment in NSCLC patients lacking targetable driver mutations. Biomarkers to identify patients at risk for early progression on ICI-mono or those who would maximally benefit from upfront ICI-chemo have not been defined. Methods: We queried the GEMINI database to identify metastatic NSCLC patients without targetable EGFR/ALK alterations who were treated with ICI-mono or ICI-chemo. Mutational profiling was performed on tissue or blood using targeted NGS. Outcome measures were defined as clinical progression free survival (PFS) or early progressive disease (PD) rate (defined as rate of 3-month progression), and their association with variables was assessed via Cox Proportional Hazards regression (PFS) or logistic regression (early PD). Predictive deep learning models were used to integrate clinicopathological factors and genomic profile. Results: 735 patients were included in this study, 269 treated with ICI-chemo and 466 with ICI-mono; 446 were treated in the first-line setting. TP53 was the most frequently altered gene (60%), followed by KRAS (37%), AR (21%), and STK11 (19%). In ICI-mono patients, alterations in STK11, ERBB2, ARID1A and CDK6 were associated with a higher likelihood of early PD; only STK11 was associated with early PD (29% vs 17%, P = 0.04) on ICI-chemo. In all patients, low PD-L1 expression and high disease burden (stage IVb and liver metastases) associated with early PD, but there were borderline significant treatment effects in favor of ICI-chemo in never smokers and patients with liver metastases and stage IVb. Shorter PFS was observed in the ICI-chemo group who had CDKN2A alterations vs wild type (median PFS: 5.1 vs 9.0 months; HR: 1.72; P = 0.01). A subgroup analysis of patients with CDKN2A alterations demonstrated preferentially worse outcomes in ICI-chemo compared to ICI-mono, with the best PFS achieved in the ICI-mono treated patients with CDKN2A point mutation. Integration of clinicogenomic features into a multivariate model with feature selection to predict early PD demonstrated a predictive performance of AUC 0.73 (vs PD-L1 alone, AUC 0.60) in the ICI-mono group, driven by liver metastases, stage IVb disease, PD-L1 expression, and STK11 alterations. These features were less predictive in ICI-chemo-treated patients, indicating a protective effect against early PD in these patients from combination chemoimmunotherapy. Conclusions: Low PD-L1, high disease burden, and STK11 alterations are markers of early PD on ICI-mono, and patients with these features may particularly benefit from upfront combination treatment with ICI-chemo to protect against early progression. Citation Format: Lingzhi Hong, Muhammad Aminu, Xuetao Lu, Maliazurina B. Saad, Pingjun Chen, Waree Rinsurongkawong, Amy Spelman, Yasir Y. Elamin, Marcelo V. Negrao, Ferdinandos Skoulidis, Carl M. Gay, Tina Cascone, Mara B. Antonoff, Boris Sepesi, Jeff Lewis, Don L. Gibbons, Ara A. Vaporciyan, Xiuning Le, J.Jack Lee, Sinchita Roy-Chowdhuri, Mark J. Routbort, John V. Heymach, Jia Wu, Jianjun Zhang, Natalie I. Vokes. Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC [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 964.

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (pEGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, pConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

NRG1 gene fusions are rare clinically actionable somatic alterations identified in 0.1% - 0.2% of all tumors. Currently, there are no approved targeted therapies for patients with NRG1 fusion-positive cancer. Previous studies have demonstrated that NRG1 fusions signal through ErbB/HER family members and that HER2 inhibition has anti-tumor activity in NRG1 fusion driven cancers. However, NRG1 binds HER4 in addition to HER3, and the role of individual HER proteins and NRG1 fusion partners have not been fully elucidated. We hypothesized that HER2 and HER4 signaling may have important roles in NRG1 fusion driven cancers, and pan-HER targeting therapies may be more effective for NRG1 fusion positive cancers than HER2-specific inhibitors alone. To test this hypothesis, we investigated the frequency of the NRG1 fusions across cBioPortal and AACR project GENIE datasets and MD Anderson’s GEMINI databases and found that the incidence of NRG1 fusions in all tumor types was 0.1%. NRG1 fusions were observed in 3.3% of patients with cervical cancers and in 1.8% of breast cancers and 1.3% of non-small cell lung cancers. The most common fusion partner was CD74 (9%) and the second most common fusion partner was SLC3A2 (4%). To determine the role of ErbB signaling in NRG1-fusion positive cancers, we engineered Ba/F3 cells to express various ErbB/HER family members and the most common NRG1 fusion partners. Then, we evaluated different strategies of targeting NRG1-fusion positive cell lines using drugs that predominantly target EGFR, HER2, EGFR/HER2, dimerization, or drugs that are pan-HER inhibitors. In Ba/F3 cells, poziotinib, a pan-HER TKI, showed potent activity against cells harboring NRG1 fusions, with IC50 values of 0.19 - 0.36 nM and relative IC50 values (IC50 value of NRG1 fusion/IC50 value of WT EGFR) of 0.04 – 0.07. TKIs targeting predominately EGFR/HER2 (afatinib, dacomitinib and neratinib) we observed modest activity with IC50 values of 6.8 – 42 nM and relative IC50 values of 0.11 – 0.68. The IC50 values of HER2-specific TKIs (58 – 122 nM) were higher than EGFR/HER2 targeting TKIs, but the relative IC50 values (0.005 – 0.015) were lower than poziotinib. Among antibodies, targeting HER2 dimerization with pertuzumab had better single agent activity (IC50 values of 95 – 156 μg/ml) than trastuzumab which had no in vitro activity. Lastly, an additive effect was seen when trastuzumab was used in combination with pertuzumab, with IC50 values of 0.79 – 1.0 μg/ml, and poziotinib with trastuzumab and pertuzumab further potentiated activity. Taken together, these data suggest that pan-HER inhibition with agents such as poziotinib alone and in combination with inhibition of dimerization appears more effective than selective EGFR/HER2 inhibition and highlights the potential of combining agents with multiple mechanisms of HER family targeting. This pan-HER strategy merits further investigation in the clinic. Citation Format: Hibiki Udagawa, Jacqulyne P. Robichaux, Yasir Y. Elamin, Junqin He, Monique B. Nilsson, John V. Heymach. Molecular landscape and ErbB family signaling in NRG fusion NSCLC: Therapeutic implications for pan-ErbB family inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1182.

TPS9156 Background: Although EGFR-targeted therapies have improved outcomes in patients with EGFR-mutant ( EGFRm) NSCLC, such as EGFR ex19del and L858R, resistance to these drugs is inevitable. BLU-945 is an investigational next-generation EGFR tyrosine kinase inhibitor (TKI) designed to suppress common activating and on-target resistance EGFR mutations, such as C797S and T790M. Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. In addition, BLU-945 has > 450-fold selectivity for C797S and T790M mutants over wildtype, advantageous for combinations with complementary EGFR-targeting agents, such as osimertinib. These combinations have shown enhanced activity in PDX models. The SYMPHONY trial (BLU-945-1101; NCT04862780) is an international, open-label, first-in-human, phase 1/2 study designed to evaluate safety, tolerability, and antitumor activity of BLU-945 as monotherapy and in combination with osimertinib in patients with EGFRm NSCLC. Methods: Key eligibility criteria include adults with pathologically confirmed metastatic NSCLC with an activating EGFR mutation, Eastern Cooperative Oncology Group performance status 0–1, and previous treatment with ≥1 EGFR-targeted TKI. Patients with asymptomatic brain metastases who are on stable doses of corticosteroids are eligible. Tumors with additional known driver alterations, including EGFR exon 20 insertions and other kinase drivers, are excluded. Primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D) and safety (phase 1); and overall response rate (ORR) by RECIST 1.1 (phase 2). Key secondary endpoints include ORR, duration of response (DOR), pharmacokinetics (PK), and pharmacodynamics (PD; phase 1); and DOR, progression-free survival, overall survival, CNS efficacy, PK, and safety (phase 2). Phase 1 dose escalation will be done using Bayesian optimal interval design; ̃85 patients will receive BLU-945 monotherapy and ̃18 will receive combination BLU-945 and osimertinib. In the phase 2 dose expansion, patients will receive BLU-945 at the RP2D of the monotherapy in 3 groups based on EGFR mutational profile: T790M and C797S (n≈37), T790M, but not C797S (n≈12), and C797S, but not T790M (n≈12). In a combination group, BLU-945 plus osimertinib will be administered at RP2D of the combination to n≈24 patients, ≥12 with both T790M and C797S mutations. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia. Clinical trial information: NCT04862780.

3006 Background: NRG1 fusions are rare oncogenic drivers found in ̃0.2% of all solid tumors. These fusions elicit ERBB3/HER3 overactivation to drive tumor growth and cancer cell survival. Currently there are no approved targeted therapies for NRG1 fusion-positive tumors. Furthermore, patients (pts) with tumors harboring NRG1 fusions have poor outcomes with standard therapies. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that suppressed tumor growth in NRG1 fusion-driven preclinical models. Here, we present initial clinical data from the CRESTONE study (NCT04383210). Methods: CRESTONE is a Phase 2, global, multicenter, open-label study of seribantumab in adult pts with locally advanced or metastatic solid tumors harboring NRG1 fusions. A dose ranging phase established the RP2D as a 3g once weekly (QW) intravenous dose administered until treatment discontinuation criteria are met. In the expansion phase, cohort 1 will enroll at least 55 pts who had received at least one prior therapy and are naïve to ERBB-targeted therapy. Exploratory cohorts 2 or 3 will enroll pts previously treated with ERBB-targeted therapies and/or tumors harboring additional molecular alterations. The primary endpoint is objective response rate (ORR) by independent central review per RECIST v1.1. Initial data from cohort 1 pts who received seribantumab 3g QW with investigator (INV)-assessed response per RECIST v1.1 are reported. Results: By JAN-13-2022, 12 pts have received seribantumab 3g QW in cohort 1. Median age was 65 years (range 44–76), 67% were female, and median number of prior therapies was 1 (range 1–5). 92% (11/12) of pts had non-small cell lung cancer (NSCLC); 5 different NRG1 fusion partners ( ATP1B1, CD74, ITG B1, SDC4, SLC3 A2) were reported by local next-generation sequencing tests. Among 10 pts evaluable for INV-assessed response, the confirmed ORR was 30%, and the disease control rate was 90% (1 complete response, 2 partial responses, 6 stable disease, 1 progressive disease). 58% (7/12) of pts remain on study treatment, including 2 pts with NSCLC who achieved objective responses with an ongoing duration of response of 6 and 8.5 months. Seribantumab 3g QW was well tolerated with no drug discontinuations or dose reductions. Across all cohorts (n = 29), the most frequently (≥20%) reported treatment-related adverse events (TRAEs) were diarrhea (38%), fatigue (34%), and rash (24%), all were grade 1 or 2. One grade 3 TRAE of vomiting occurred; there were no Grade 4 or 5 TRAEs. Efficacy analysis is ongoing and updated efficacy data from evaluable pts in cohort 1 will be presented. Conclusions: Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study. Clinical trial information: NCT04383210.

TPS9142 Background: Although 3rd-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, are highly effective in front-line metastatic EGFR-mutated ( EGFRm) NSCLC, treatment resistance ultimately occurs, including the emergence of the on-target C797X mutation for which there are no approved TKIs. BLU-701 is an investigational, reversible, brain-penetrant, wildtype-sparing oral TKI with nanomolar potency on common activating (exon 19 deletion and L858R) and C797X resistance mutations (Tavera L et al. AACR 2022). BLU-701 has shown promising preclinical data, including antitumor central nervous system (CNS) activity that may improve patient outcomes. Additionally, combining BLU-701 with standard of care therapies may provide enhanced disease control across multiple lines of treatment, including against heterogenous tumors, in patients with EGFRm NSCLC. Methods: HARMONY (NCT05153408) is an ongoing, global phase 1/2, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BLU-701 as a monotherapy or in combination with osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC. Key inclusion criteria include patients ≥18 years of age with metastatic EGFRm NSCLC; Eastern Cooperative Oncology Group performance status 0–1; and previous treatment with ≥1 EGFR-targeted TKI. Patients in the phase 2 monotherapy part must harbor an EGFR C797X resistance mutation (locally assessed). Key exclusion criteria are tumors harboring EGFR T790M mutations, EGFR exon 20 insertions, or other known driver alterations, including KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include ORR (phase 1), duration of response, and PK/PD (phase 1 and phase 2); disease control rate, progression-free survival, overall survival, antitumor CNS activity, and safety (phase 2). The phase 1 dose escalation will adopt a Bayesian optimal interval design. Patients will be enrolled into 3 treatment cohorts: part 1A (n≈40–80; BLU-701), part 1B (n≈35; BLU-701 + osimertinib), and part 1C (n≈18; BLU-701 + carboplatin and pemetrexed). Patients in the phase 2 dose expansion (n≈24) will be treated at the RP2D of BLU-701 as monotherapy. Patients may receive treatment until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment in this study has started, and sites will be open across North America, Europe, and Asia. Clinical trial information: NCT05153408.

9049 Background: Primary resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. Here, we describe the clinical outcome of patients who experienced radiologic progression within 12 weeks of therapy with nivolumab and ipilimumab (I+N) for metastatic non-small cell lung cancer (mNSCLC). Methods: The LONESTAR study is an ongoing phase III study (NCT03391869). Study enrolls patients with immunotherapy naïve mNSCLC (prior chemotherapy is allowed). All patients receive I+N for 12 weeks and are randomized to experimental therapy vs. control arm if they did not have disease progression. Patients who experience radiologic progression per RECIST v1.1 are not randomized and removed from the study. Treatment beyond progression is allowed if they clinically benefit from the systemic therapy. We prospectively collected clinicopathologic and radiologic outcome data from patients who experienced radiologic progression within 12 weeks of I+N therapy and have not randomized to investigational therapy. We described the primary progression pattern. We collected subsequent treatment, radiologic, and toxicity data and calculated clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results: Of the 194 patients who received at least one dose of I+N therapy, 72 patients had clinical and/or radiologic progression at ≤ 12 weeks. Thirty-five (35; 48%) patients did not receive subsequent treatment, 21 (29%) patients received subsequent 2nd line systemic therapy, and 16 (22%) patients were continued on I+N beyond radiologic progression due to ongoing clinical benefit. Among patients treated with 2nd line therapy, 13 patients were treated with platinum doublet +/- anti-PD-(L)1, seven (7) patients were treated with single-agent chemotherapy +/- VEGF inhibitor, and one (1) patient was treated with targeted therapy. The PFS for the 2nd line therapy was 6.5 months (95%CI: 4.8, 8.9), and OS was 10.4 months (95%Cl: 6.6, 16.1). Among the 16 patients treated with I+N beyond progression, 13 had a mixed response to induction therapy, where primary progression was most frequently observed in mediastinal lymph nodes. LCT with radiotherapy was utilized with I+N in 10 patients. The median duration of post-progression treatment with I+N plus LCT was 8.7 months (95%Cl: 5.9, 22.3) and 5.6 months (95%Cl 4.4, 11.5) with I+N alone. The OS was 19.5 months (95% CI: 6.2,18.7). Conclusions: In this study cohort, primary resistance to I+N was observed in 37% of the patients, and in a subset of these patients treated with post-progression I+N, either alone or in combination with LCT, durable clinical benefit was observed. Further studies are warranted to identify which patients are most likely to benefit from post-progression I+N. Clinical trial information: NCT03391869.

9105 Background: The aurora kinase and mTOR pathways are implicated in resistance to EGFR inhibitor osimertinib. Here, we investigated the safety and efficacy of the aurora kinase inhibitor alisertib and the mTOR inhibitor sapanisertib in combination with osimertinib. Methods: This is a phase 1b study with dose finding and expansion portions (NCT04479306). The dose finding portion used a Bayesian optimal interval (BOIN) design to assess two arms: osimertinib 80 mg daily in combination with alisertib 20 mg, 30 mg, and 40 mg daily day 1-21 of 28-day cycle (osi-ali arm) and osimertinib 80 mg daily in combination with sapanisertib 2 mg and 3 mg daily (osi-sapa arm). Dose limiting toxicities (DLTs) were predefined in the protocol. Patients with EGFR (L858R/exon 19 deletion) mutant NSCLC whose disease have progressed on osi and up to one additional line of systemic therapy were assigned, at investigator discretion, to either study arm. Tumor biopsy was mandatory at study entry and optional upon progression. Results: As of February 1, 2022, 40 patients are enrolled (20 in each arm). One DLT was observed in each arm: grade 3 nausea in ali-osi arm and grade 3 AST elevation in osi-sapa arm. Grade 3 treatment emergent adverse events (TEAEs) occurred in 10% of each arm, and no grade 4 TEAEs were observed. The most common TEAEs in osi-ali arm was leucopenia (45%) and anemia (35%) while in osi-sapa arm, hyperglycemia (45%) and stomatitis (40%). In osi-ali arm (n = 20), median progression free survival (mPFS) was 1.9 months while objective response rate (ORR) and disease control rate (DCR) were 5% (95% CI: 0.1 ̃ 24.9%) and 40% (95% CI: 19.1 ̃ 63.9%), respectively. In osi-sapa arm (n = 16, evaluated for response to date), mPFS was 4.6 months while ORR and DCR were 12.5% (95% CI: 1.6 ̃ 38.3%) and 68.7% (95% CI: 35.7 ̃ 82.7%), respectively. Conclusions: Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib. Clinical trial information: NCT04479306.

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)

Background An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient’s tumor that can confer clinical efficacy or drug resistance. Methods The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Results Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Conclusions Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations.Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase.In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFREGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFR

PURPOSE: In oropharyngeal squamous cell carcinoma (OPC), high CD8-positive tumor-infiltrating lymphocytes (CD8(+)TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab plus tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8(+)TIL density, safety, and efficacy in OPC patients. PATIENTS AND METHODS: Patients with newly diagnosed stage II-IVA OPC or locoregionally-recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab plus tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8(+)TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. RESULTS: Of 28 eligible patients (14 per arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8(+)TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P=.97, 95%CI:(−1.07,2.28)). In each group, 6 patients (43%, 95%CI:(17.66,71.14)) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8(+)TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8(+)TIL change in patients with a MPR was seen (P=.059, 95%CI:(−0.33,3.46)). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. CONCLUSIONS: Durvalumab plus tremelimumab did not increase CD8(+)TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC. Clinicaltrials.gov identifier NCT03144778

Background HER2 is overexpressed in 10-25% of gastric cancers (GCs). The association of PI3K pathway activating mutations with HER2 overexpression, or the impact of aberrant PI3K pathway signalling on response to trastuzumab (Tr) in GC has not been described. In HER2-positive breast cancer, targeting the PI3K pathway can overcome resistance to HER2-targeted therapies; however the role of PI3K inhibitors in sensitizing HER2-positive GCs to Tr or in overcoming Tr resistance is unknown. Methods Tumour samples from 69 GC patients were stratified into HER2-positive (n = 29) and HER2-negative (n = 40) groups. Mass spectrometry-based genotyping (Agena Bioscience) was used to analyse 105 hotspot somatic mutations in PIK3CA, EGFR, ERBB2, ERBB3 and ERBB4 in the tumours and in a panel of HER2-positive GC cell lines (N87, OE19, ESO26 and SNU16). The anti-proliferative response to the PI3K inhibitor copanlisib alone and in combination with the HER2-targeted therapies Tr and lapatinib was assessed in vitro. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months; p = 0.0032). PIK3CA, EGFR and ERBB mutations occurred more frequently in HER2-negative tumours than HER2-positive tumours, but had no impact on progression free or overall survival. In vitro OE19 cells were resistant to copanlisib, while all other cell lines were sensitive, independent of PIK3CA mutation status, with IC50s ranging from 23.4nm (N87) to 93.8nm (SNU16). All cell lines except SNU16 were sensitive to lapatinib with IC50s ranging from 0.04µM to 1.5µM. OE19 and SNU16 were resistant to Tr. The combination of lapatinib and copanlisib is synergistic in ESO-26 and OE-19 cells (ED50: 0.83±0.19 and 0.88±0.13, respectively) and additive in N87 cells (ED50:1.01±0.55). The combination of copanlisib and Tr significantly improved growth inhibition compared to either therapy alone in N87, ESO26 and OE19 cells (p Conclusions Copanlisib is an effective monotherapy in some HER2-positive GC cell lines. Combinations of copanlisib and Tr offer greater benefit than either drug alone, and may restore sensitivity to Tr in cells with intrinsic resistance to Tr. The addition of copanlisib to HER2 targeted therapy warrants further investigation in HER2-positive GC. Legal entity responsible for the study The authors. Funding North East Cancer Research and Education Trust (NECRET). Disclosure All authors have declared no conflicts of interest.

Radiotherapy combined with three weekly 100 mg/m2 of cisplatin is the accepted standard of care in head and neck squamous cell carcinoma. However, this regimen is associated with severe toxicities with devastating effects on patients. Alternative protocols like weekly 40 mg/m2 have been used in an attempt to reduce toxicities. The main objective of the present study is to identify the dose intensities and toxicities of weekly cisplatin in patients treated in a tertiary centre over a 12 month period. Included patients had squamous cell carcinoma arising in the oral cavity, oropharynx, larynx, or hypopharynx. Patients were excluded if they had nasopharyngeal squamous cell carcinoma, distant metastasis or if they had prior treatment for head and neck cancer excluding neck dissection. During the study period, 52 patients met the inclusion criteria and their data were retrospectively obtained from the patients' database of St James hospital, Dublin. The median age of the study cohort was 54 years (range 33-73). Of the patients, 40 (76.9 %) were male and 12 (20.1 %) were female. The primary tumour sites were as follows: oral cavity and oropharynx in 38 (73 %), larynx in 10 (19 %), and hypopharynx in 4 (8 %). In total, 33 (63.5 %) patients had stage IV disease, while 19 (36.5 %) had stage III disease. Treatment was definitive in 35 (67 %) patients and adjuvant in 17 (35 %). Full-dose radiotherapy was achieved in 50 (96 %) patients. Only 22 (42.3 %) patients completed the intended six cycles of chemotherapy. Cumulative dose of 200 mg/m2 or more was reached in 37 (71 %) patients. The acute adverse effects included grades 3 and 4 mucositis, which occurred in 22 (43.3 %) and 6 patients (12 %), respectively. Grade 3 and 4 neutropenia occurred in six (11.5 %) and three (5.7 %) patients, respectively. The only other haematological toxicity was grade 3 anaemia in 20 (38.4 %) patients. There was no grade 3 or 4 renal toxicity among the study cohort, although grade 2 was observed in six (11.5 %) patients. Death occurred in one patient due to neutropenic septicaemia. In conclusion, weekly cisplatin is associated with moderate to severe toxicities and might lead to suboptimal chemotherapy delivery. More prospective clinical studies are required to determine the optimal chemoradiation regimen in head and neck squamous cell carcinoma.

Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immune-response and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

Background: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2) over expression and gene amplification metastatic gastric cancer. Here we present the prevalence of HER2 positive gastric cancer in an Irish population, the use of Trastuzumab in first line and beyond progression. Methods: The study was conducted in St James’s Hospital, Dublin. A retrospective analysis of the date of patients with HER2 positive gastric cancer over a period of 3 years was carried out. Her2 positive was defined as immunohistochemistry (IHC) score of +3, of IHC score of +2 and increased gene copy number by fluorescence in situ hybridization (FISH). Overall survival was calculated from the day of initiation of treatment with Trastuzumab until death. Results: During the study period 140 patients with gastric and gastro-esophageal junction adenocarcinoma were treated. Out of those, 30 (21.4%) had HER2 positive disease. Among HER2 positive disease patients 18 (12.8%) were treated with first line Trastuzumab containing regimen with a median overall survival of 13 months. Nine (50%) developed progressive disease while on Trastuzumab and of those, 4 (22.2%) patients continued on Trastuzumab beyond progression, two (11.1%) of whom achieved stable disease and a prolonged survival. Conclusion: HER2 positivity rate in an Irish population with advanced gastric and gastro-esophageal junction adenocarcinoma is 21.4%. Treatment with Trastuzumab in the first line in combination with chemotherapy is a reasonable approach. Continuation of Trastuzumab beyond progression is a feasible strategy that requires further exploration.

Background Inflammatory myofibroblastic tumours (IMTs) are rare sarcomas that were first described in the lung. They are composed of myofibroblastic mesenchymal spindle cells accompanied by an inflammatory infiltrate of plasma cells. Complete resection is the treatment of choice. There is currently no standard treatment for inoperable or recurrent disease. Expression of ALK protein triggered by ALK gene rearrangement at chromosome 2p23 has been found in 36%-60% of IMTs. Case report We report a rapid early response to crizotinib as neoadjuvant therapy, enabling surgical excision of a large ALK(-translocated IMT, which resulted in complete disease clearance. To the best of our knowledge, this is the first case in the literature of a patient with IMT in whom crizotinib was used successfully in the neoadjuvant or curative setting.

Angiogenesis or new vessel formation is essential for tumour growth and progression. Therefore, targeting angiogenesis has been an attractive strategy in the treatment ofcancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody thattargets vascular endothelial growth factor-A (VEGF-A) - a key molecular player inangiogenesis. Bevacizumumab has shown clinical efficacy in phase III clinical trials inseveral advanced solid malignancies. The clinical efficacy of bevacizumumab isprimarily due to its antiangiogenic effects; however, there are direct antitumor effectsand immunomodulatory effects. Enhancing the immune system to restore itsantitumour activity has been utilized successfully in clinical setting. In this article we willdiscuss the possible immunomodulatory effects of the most clinically usedantiangiogenic agent; bevacizumumab.