Ballhausen et al. Page 1247

Activation of PI3K signaling has been identified previously as a mechanism of resistance to hormone therap. and HER2-targeting agents in breast cancer. Ballhausen and colleagues performed a dose-escalation phase I trial to assess the combination of the mTOR inhibitor everolimus, the aromatase inhibitor letrozole, and the HER2 antibody trastuzumab in patients with breast cancer and other solid tumors. This combination had an acceptable safety profile. At the recommended phase II dose, 5/32 patients (16%) showed a partial response to treatment, and these responses all occurred in women with breast cancer. Patients with HER2 amplification in cfDNA at baseline had shorter progression-free and overall survival compared to patients that lacked this alteration. These results support further clinical investigation of this combination, particularly in women with breast cancer.

de Haan et al. Page 1256

Radiosensitizers have the potential to improve locoregional tumor control. PARP inhibitors like olaparib are promising radiosensitizers that compare favorably in toxicity and radiosensitization potential to platinum agents. Improvement of locoregional control is still needed in locally advanced non-small cell lung cancer (NSCLC) because around one-third of patients experience a locoregional failure after platinum-based concurrent chemoradiotherapy. In this study, de Haan and colleagues identify a maximum tolerated olaparib dose in combination with locoregional radiotherapy for NSCLC taking into account pharmacodynamics relevant for radiosensitization and long-term toxicity. Two-year locoregional control was 84% with this treatment strategy. To avoid severe pulmonary late toxicity, subsequent studies should explore more conformal radiotherapy schedules with improved pulmonary sparing.

Patnaik et al. Page 1267

Although checkpoint inhibition has been a major advance in clinical oncology, many patients will not respond or will develop resistance to this treatment strategy. The combination of checkpoint inhibitors with targeted therapies is thought to be a potential strategy to improve response. Patnaik and colleagues performed a phase I study assessing LY3300054, a PD-L1 inhibitor, with ramucirumab, abemaciclib, or merestinib. LY3300054 had comparable pharmacokinetic, pharmacodynamic, safety and antitumor activity to approved PD-L1 inhibitors. One patient in each study arm showed a partial response to treatment lasting greater than 7 months. The findings from this study suggest that LY3300054 is a safe and promising immunotherap. with potential utility in combination with targeted agents.

Wang et al. Page 1305

The development of theranostic agents enabling imaging and treatment is changing the standard care in many diseases including prostate cancer. Wang and colleagues demonstrate the development of a novel immunoPET agent for the detection of prostate cancer, named [89Zr]DFO-YS5. The probe demonstrates high tumor to background ratios in cell line and patient-derived xenografts, producing excellent image contrast. Importantly, the agent was able to detect a variety of prostate tumor types, including adenocarcinoma, neuroendocrine cancer, and prostate-specific membrane antigen (PSMA)-negative tumors. [89Zr]DFO-YS5 demonstrates promise for clinical translation for the detection of prostate cancer.