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A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody-drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In HER2-mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention.

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Preliminary results from the phase 1 TROPION-PanTumor01 study demonstrate that Dato-DXd has encouraging antitumor activity and a manageable safety profile in patients with non-small cell lung cancer (NSCLC) (Meric-Bernstam, ASCO 2021) and those with triple-negative breast cancer (TNBC) (Bardia, ESMO BC 2021). Updated results from the TNBC cohort are presented here. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multi-center, open-label, 2-part study evaluating Dato-DXd in previously treated patients with solid tumors. Based on the dose-escalation results in patients with NSCLC, Dato-DXd 6 mg/kg intravenously every 3 weeks is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies. Two patients with TNBC received Dato-DXd 8 mg/kg prior to selection of 6 mg/kg for dose expansion. Safety and efficacy were assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). Results: As of the April 6, 2021, data cutoff, 43 patients with TNBC had received ≥1 dose of Dato-DXd, with 27 patients (63%) continuing and 16 patients (37%) discontinuing treatment all due to disease progression. The median age was 53 years (range, 32-82 years). Forty-one patients (95%) had received ≥2 prior lines of therapy; 19 patients (44%) had received prior immunotherapy and 7 (16%) had received prior sacituzumab govitecan. The median duration of treatment was 2.8 months (range, 0.7-6.9 months). The median follow-up was 3.9 months (range, 0.3-9.2 months). Among 38 patients evaluable for response, the ORR by BICR was 39% (15 partial responses [PR]), with 12 confirmed and 3 pending confirmation. The disease control rate was 84% (32/38). The median time to response was 1.35 months (1.2-3.2 months) for the 12 confirmed PRs. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 95% and 35% of patients, respectively; 2 events were grade 4 and 0 grade 5. The most common TEAEs (any grade [≥30%], grade ≥3) included nausea (58%, 0%), stomatitis (53%, 9%), alopecia (35%, N/A), vomiting (35%, 2%), and fatigue (33%, 7%). One patient had grade 3 decreased neutrophil count; no cases of grade ≥3 diarrhea were observed. No cases of treatment-related interstitial lung disease as adjudicated by an independent committee were reported. Serious TEAEs were observed in 5 patients (12%); no TEAEs were associated with death. Dose reductions occurred in 9 patients due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision (multiple counts per TEAE). Three patients had dose interruptions due to stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain. No patients discontinued treatment due to adverse events. Conclusions: Preliminary results showed that Dato-DXd demonstrates promising antitumor activity with a manageable safety profile in patients with previously treated advanced/metastatic TNBC; confirmatory studies in patients with breast cancer are warranted. Citation Format: Ian Krop, Dejan Juric, Toshio Shimizu, Anthony Tolcher, Alexander Spira, Toru Mukohara, Aaron E. Lisberg, Takahiro Kogawa, Kyriakos P. Papadopoulos, Erika Hamilton, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Ferdinand Guevara, Takahiro Jikoh, Yui Kawasaki, Funda Meric-Bernstam, Aditya Bardia. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-05.

The adult central nervous system has only a limited capacity for axonal regeneration. In this study, fibroblast growth factor-2 (FGF-2) was injected once into the spinal cord tissue around the injury site immediately after complete spinal cord transection in rats. This treatment markedly improved the locomotor function of the animals. Histological analysis demonstrated that tissue composed of FGF-2-induced fibronectin-positive cells (FIFs) had infiltrated the injury site and filled large cystic cavities, into which numerous axons with growth-associated protein-43 immunoreactivity penetrated. The FIFs could also be cultured from the intact spinal cord tissue, demonstrating that they were resident in the noninjured spinal cord. They had a spindle-shaped morphology and enhanced expression of mRNAs of N-cadherin and neurotrophic factors, suggesting the beneficial properties of the FIFs for axonal regeneration. Thus, these results argue for the continual use of autologous transplantation as a novel and promising cell therapy for the treatment of spinal cord injury.

and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%. Conclusion: In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]