PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.

PURPOSE: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2–mutant ( HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non–small-cell lung cancer (mNSCLC). METHODS: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review. RESULTS: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively. CONCLUSION: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

Background: Better biomarkers are needed to predict treatment outcome in NSCLC patients treated with anti PD-(L)1 checkpoint inhibitors. PD-L1 immunohistochemistry has limited predictive value, possibly due to tumor heterogeneity of PD-L1 expression. Noninvasive PD-L1 imaging using ⁸⁹Zr-durvalumab might provide a better reflection of tumor PD-L1 expression and can therefore support treatment decision making. Patients and Methods: NSCLC patients eligible for second line immunotherapy treatment were enrolled. Patients received two injections of ⁸⁹Zr-durvalumab; one without a preceding dose of unlabeled durvalumab (‘tracer dose only’) and one with a preceding dose of 750 mg durvalumab, directly prior to tracer injection. Up to four PET/CT scans were obtained after tracer injection. Post-imaging acquisition, patients were treated with 750mg durvalumab every two weeks. Tracer biodistribution and tumor uptake were visually assessed and quantified as standardized uptake value (SUV) and both imaging acquisitions were compared. Tumor tracer uptake was correlated with PD-L1 expression and clinical outcome, defined as treatment response to durvalumab treatment. Results: Thirteen patients were included and ten completed all scheduled PET scans. No tracer related adverse events were observed and all patients started durvalumab treatment. Biodistribution analysis showed ⁸⁹Zr-durvalumab accumulation in the blood pool, liver and spleen. Serial imaging showed that image acquisition 120 hours post injection delivered the best tumor to blood pool ratio. Most tumor lesions were visualized with the tracer-dose only versus the co-injection imaging acquisition (25% vs 13.5% of all lesions). Uptake heterogeneity was observed within (range SUVpeak 0.2 to 15.1) and between patients. Tumor uptake was higher in patients with treatment response or stable disease, compared to patients with disease progression according to RECIST 1.1. However, this difference was not statistically significant (median SUVpeak 4.9 vs 2.4, P = 0.06). SUVpeak correlated better with the combined tumor and immune cell PD-L1 score than with PD-L1 expression on tumor cells, although both were not statistically significant (P = 0.06 and P = 0.93, respectively). Conclusion:⁸⁹Zr-durvalumab was safe without any tracer related adverse events and more tumor lesions were visualized using the tracer dose only imaging acquisition. ⁸⁹Zr-durvalumab tumor uptake was higher in patients with response to durvalumab treatment, but did not correlate with tumor PD-L1 IHC.