Ron Bose

Studies suggest that the human trophoblast cell-surface antigen (TROP2) is highly expressed in most lung cancers and is associated with poor prognosis. Currently, there are no TROP2-directed ADCs approved for the treatment of lung cancer patients. IMMU-132 ADC (Sacituzumab govitecan) is a TROP-2-directed ADC recently approved for metastatic triple-negative breast cancer and urothelial cancer. However, its role in non-small cell carcinoma (NSCLC) has not been explored. Here, we examined the impact of IMMU-132 alone and in combination with radiation on NSCLC cells in vitro and in vivo. We found cell surface expression of TROP-2 on NSCLC cell lines, internalization of IMMU-132, induction of cell cycle arrest at the G2/M phase, and promotion of programmed cell death (apoptosis) following irradiation. Furthermore, IMMU-132 enhanced radiosensitivity by decreasing clonogenic survival through increased DNA double-strand break formation (as indicated by the γH2AX level), modulating DNA damage repair, inhibiting survival pathways, and inducing PARP-mediated apoptosis. In vivo, the combination of IMMU-132 and radiation therapy increased tumor control and improved overall survival in mice bearing H441 and H460 cell xenografts, as well as in the syngeneic LLC tumor. Tumor radio-sensitization with IMMU-132 promotes the inhibition of prosurvival signaling (PI3K/AKT/mTOR/, MEK/ERK) together with induced apoptosis by increasing PARP, cleaved caspase-3 and reducing anti-apoptotic proteins (BCL-xL, BCL-2, XIAP) as well as modulating DNA damage repair (ATM, ATR, RAD51, p53, DNA-PK). Together, our data suggests that the targeted delivery of IMMU-132 radiosensitizer at sub-therapeutic doses could broaden the therapeutic window of radiation therapy in lung cancer and may decrease the possibility of side effects. Hence, the combination of IMMU-132 and radiation therapy could be a promising therapeutic strategy for NSCLC.

Purpose:Human epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib + trastuzumab (N + T; neratinib 240 mg/day, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts. Patients and Methods:Primary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORRfirst); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment. Results:Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2−73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2−61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2−73.8) and 47.1% (95% CI, 23−72.2), respectively; median PFS times were 2.89 (95% CI, 0.95−5.52) and 6.24 months (95% CI, 2.10−8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation. Conclusions:N + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor–positive or –negative metastatic breast cancer with activating HER2 mutations.See related commentary by Lloyd et al., p. 3715

Treatment duration and responses in patients receiving either neratinib monotherapy or N + T. Values in bold indicate patients for whom longitudinal ctDNA sequencing was available. PD, progressive disease.

Best change in tumor from baseline and corresponding histology and central biomarker analysis. mPERCIST, modified PET RECIST; PD, progressive disease; VUS, variant of uncertain significance.

A,HER2 mutation VAF at pretreatment, on-treatment, and EOT stages in patients treated with either neratinib monotherapy or N + T. Note: Patient 21 (PR; treated with N + T) did not have an on-treatment sample and was therefore not included in this figure. B, Emergent mutations at progression in ctDNA from patients who experienced a clinical response. Circle sizes are approximately proportional to VAFs. Hollow circles indicate mutation not detectable at that time point. mCR, metabolic CR; mSD, metabolic SD; N, neratinib; PD, progressive disease; T, trastuzumab.

Baseline demographic and clinical characteristics.

Table 2 from Efficacy and Genomic Analysis of HER2-Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial

Most common treatment-emergent adverse eventsa.