Sunvozertinib (DZD9008) is a rationally designed EGFR Exon20ins inhibitor with wildtype selectivity. Results from the ongoing phase 1/2 studies showed sunvozertinib’s strong anti-tumor activity and encouraging safety profile. Based on these data, sunvozertinib was granted the Breakthrough Therapy Designation by both US FDA and China NMPA. Here we present sunvozertinib’s safety and efficacy results in advanced NSCLC patients with EGFR Exon20ins post platinum-based chemotherapies.

Folate receptor α (FRα), a cell-surface protein encoded by the folate receptor 1 gene, is upregulated in epithelial ovarian cancers and lung adenocarcinomas. AZD5335 is an antibody-drug conjugate comprising an antibody portion that binds with high affinity to FRα conjugated to a topoisomerase 1 inhibitor (TOP1i) payload. Upon binding, AZD5335 releases TOP1i within the cell. The TOP1i payload then traps TOP1 on the replicating DNA and induces DNA double-strand breaks, ultimately resulting in cell death. AZD5335 is active in preclinical models of high-grade ovarian cancer (Gymnopoulos et al. Presented at AACR 2023; abstract LB025). FONTANA (NCT05797168) is a modular, first-in-human, open-label, multicentre study of AZD5335 in patients with advanced solid tumours. The study will evaluate AZD5335 as monotherapy in patients with ovarian cancer or lung adenocarcinoma (Module 1), or AZD5335 in combination with AZD5305, a selective poly(ADP-ribose) polymerase 1 inhibitor, in patients with ovarian cancer (Module 2). Each module consists of a dose-escalation and dose-optimisation cohort. Key features of this study include the use of randomised dose-optimisation cohorts and a Bayesian-logistic regression model-based dose escalation in Module 2. Eligible patients are aged ≥18 years, ECOG performance status 0–1, must have received prior therapy, and have adequate organ and marrow function. Asymptomatic and stable brain metastases are allowed. The primary objectives are to assess the safety and tolerability, and to establish the dose limiting toxicity. Secondary objectives include assessment of objective response rate, duration of response, disease control rate, and progression-free survival by RECIST v1.1, and overall survival; characterising the pharmacokinetics of AZD5335 when given as monotherapy or in combination; and assessing immunogenicity. The study will be open to recruitment by 25 May 2023. NCT05797168. This study was funded by AstraZeneca. Medical writing support for this abstract, under the direction of the authors, was provided by Asad Mustafa of Ashfield MedComms, an Inizio company, and was funded by AstraZeneca. AstraZeneca. AstraZeneca.

Sunvozertinib (DZD9008) is a rationally designed, irreversible EGFR inhibitor targeting EGFR mutations with wild-type EGFR selectivity. Primary analysis of two ongoing pivotal studies (WU-KONG1 [NCT03974022] and WU-KONG6 [NCT05712902 & CTR20211009]) have demonstrated promising efficacy and safety of sunvozertinib in advanced NSCLC patients with EGFR Exon20 insertion mutations (exon20ins) in ≥ 2nd line settings. Herein, we reported preliminary results of sunvozertinib in treatment naïve EGFR exon20ins NSCLC.

Activating mutation KRASG12C is the most common of all KRAS mutations in advanced non-small cell lung cancer (NSCLC), accounting for 13-16% of lung adenocarcinoma. Sotorasib is the first-in-class specific, irreversible KRASG12C inhibitor. In the pivotal Phase III CodeBreaK 200 trial, sotorasib was associated with a 34% decrease in the relative risk of disease progression or death, and superior objective response rate (ORR) of 28.1% compared to 13.2% with docetaxel in previously treated NSCLC. The mechanisms of resistance associated with sotorasib are diverse, and hence combinatory treatment strategies are being investigated.

Abstract Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non–small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599

Prior studies have shown benefit of PD-(L)1/CTLA-4 blockade in NSCLC, especially in PD-L1 negative tumors; however, this benefit is limited by toxicity. MEDI5752 is a PD-1/CTLA-4 bispecific antibody engineered to preferentially bind CTLA-4 in PD-1+ activated T cells, yielding greater T cell proliferation than possible with doses feasible in the clinic (Tran, AACR 2022). Here we present results in 1L non-squamous (Nsq) NSCLC from an ongoing phase 1b/2 study (NCT03530397). Patients (pts) were enrolled into randomized (R) and single arm (S) cohorts. In the R cohort, pts received CP x 4, followed by pemetrexed maintenance + either 1500 mg Q3W MEDI5752 (M1500+C) or P (P+C). In the later S cohort, pts received 750 mg Q3W MEDI5752 + CP (M750+C). The primary endpoint was objective response rate (ORR) per RECIST v1.1. As of 12 July 2022, 105 pts were enrolled. We present the results in 91 pts: 41 pts in the R cohort, and the first 50 pts in the S cohort with at least 8 weeks of follow-up. Baseline characteristics were similar between M1500+C (n=20; 45% PD-L1<1%) and P+C cohorts (n=21; 47.6% PD-L1<1%). DOR, PFS and OS were higher in M1500+C vs P+C in ITT and PD-L1<1% (see table). High Gr3 TRAE (70%) and discontinuation due to TEAE (TEAE-DC; 70%) at M1500+C led to exploring a lower dose of MEDI5752. In M750+C (n=50; 70% PD-L1<1%), at median follow-up of ∼3.9 months, emerging efficacy shows 44% ORR in ITT and 48% in PD-L1<1% and improved safety profile (Gr3 TRAE 32%, TEAE-D/C 20%). M1500+C and M750+C led to greater increase in T cell proliferation (and clonal expansion in M1500+C) than P+C, consistent with pharmacodynamic (PD) effects of CTLA-4 blockade; clonality data on M750+C pending.Table: LBA56Efficacy (Data cut-off 12 July 2022)M1500+CITT, n=20 (PD-L1<1%, n=9)P+CITT, n=21 (PD-L1<1%, n=10)Median follow-up, mo22.814.5Objective response rate (ORR), % (95% CI)50.0 (27.2–72.8)47.6 (25.7–70.2)ORR in PD-L1<1%55.6 (21.2–86.3)30.0 (6.7–65.2)Median duration of response (mDOR), mo (95% CI)20.5 (4.1–NE)9.9 (2.8–NE)mDOR in PD-L1<1%13.8 (4.4–NE)NR (4.3–NE)Median progression-free survival (mPFS), mo (95% CI)15.1 (5.5–NE)8.9 (4.2–15.0)mPFS in PD-L1<1%13.4 (4.0–NE)9.0 (1.4–15.0)Median overall survival (mOS), mo (95% CI)NR (16.4–NE)16.5 (12.8–NE)CI, confidence interval; ITT, intent-to-treat; mo, months; NE, not evaluable. Open table in a new tab CI, confidence interval; ITT, intent-to-treat; mo, months; NE, not evaluable. M1500+C improved DOR, PFS and OS compared to P+C in a randomized signal finding trial in 1L Nsq NSCLC. Emerging data with M750+C shows similarly encouraging efficacy, especially in PD-L1<1% subgroup, with improved tolerability.

Small cell lung cancer (SCLC) is an aggressive cancer, often metastatic at presentation and with a poor prognosis. Study of patterns of care enables the evaluation of the dissemination of state-of-the-art cancer therapy and diagnostics into community oncology practice to identify patient-, provider-, and system-level factors that are associated with receipt and utilization of cancer care and survival outcomes. The patterns of care for SCLC remain incompletely defined in the Australian population.

While platinum-based chemotherapy is the standard of care for the 1st line treatment of NSCLC with EGFR Exon20 insertion (Exon20ins) mutations, there is no consensus for further treatment once disease progresses. EGFR TKIs, anti-PD(L)1, anti-angiogenesis, among others, are frequently used. Sunvozertinib is a rationally designed EGFR Exon20ins inhibitor with wildtype selectivity. Results from the ongoing phase 1/2 studies showed sunvozertinib’s strong anti-tumor activity and benign safety profile.

Background Stimulator of interferon (IFN) genes (STING) is a protein that promotes type I IFN production essential for T-cell activation. In this study, we aim to characterize STING expression comprehensively using The Cancer Genome Atlas (TCGA) database, cell lines, and patient tumor samples stained with immunohistochemistry. Methods Two cohorts were evaluated comprising 721 non-small cell lung cancer (NSCLC) patients and 55 NSCLC cell lines for STING and cyclic GMP-AMP synthase (cGAS) expression using immunohistochemistry. Moreover, an independent cohort of n = 499 patients from the TCGA database was analyzed. Methylation was evaluated on STING and cGAS in five STING-negative NSCLC cell lines. Results STING RNA expression positively correlates with T cell function and development genes, negatively correlates with cell proliferation and associated with increased survival (5-year-overall survival [OS] 47.3% vs. 38.8%, p = 0.033). STING protein expression is significantly higher in adenocarcinoma (AC) and is lost with increasing stages of AC. STING-positivity is significantly higher in mutant EGFR and KRAS tumors. STING-positive NSCLC patients identified with immunohistochemistry (H-score > 50) have increased survival (median OS: 58 vs. 35 months, p = 0.02). Treatment of STING-negative cell lines with a demethylating agent restores STING expression. Conclusions STING is ubiquitously expressed in NSCLC and associated with T cell function genes, AC histology, EGFR, and KRAS mutations and improved overall survival.

Retrospective analysis of NaPi2b expression amongst 438 resected non-small cell lung cancer specimens. High NaPi2b expression noted in 34.5% cases overall and 65.9% of adenocarcinoma cases. Early phase clinical trials with antibody drug conjugates utilizing NaPi2b are currently in progress in non-small cell lung cancer cohorts. Background: NaPi2b is a multi-transmembrane sodium-dependent phosphate transporter expressed at normal levels in several organs, including lung. High expression levels have been reported in various tumors including breast, thyroid, ovarian and non-small cell lung cancer. To date evaluation of NaPi2b expression has mostly been restricted to smaller lung cancer cohorts. Methods: Analyses were performed on archival formalin fixed paraffin embedded primary tumor specimens from patients who had undergone curative intent resection at an Australian tertiary hospital. Tissue microarrays were constructed and stained with the chimeric anti-NaPi2b antibody, MERS67. Semi-quantitative H-scores (range 0 - 300) were calculated for each core tissue sample (H-score = %tumor cells staining for NaPi2b multiplied by staining intensity). An overall average H-score was reported for each specimen, with a cut-off score of 50 considered positive. Results: Of 438 cases, high NaPi2b expression was observed in 151 (34.5%) overall, high expression in 137 of 208 (65.9%) adenocarcinoma cases, and 5 of 179 (2.8%) squamous cases (P < .0001). High NaPi2b expression was associated with female sex, EGFR or KRAS mutation, and TTF1 positivity (adenocarcinoma cases only). High NaPi2b expression was associated with improved overall survival (median 54 vs. 35 months, P = .029). Conclusion: High NaPi2b expression was noted in a significant subset of adenocarcinoma cases, and in particular amongst those who were TTF1+, or exhibited EGFR or KRAS mutations. This agrees with earlier reports and highlights the significance that NaPi2b may have a role as a possible target for delivery of cytotoxic agents via antibody-drug conjugate models for some patients with lung adenocarcinoma. (C) 2021 Elsevier Inc. All rights reserved.