PF-06664178

After the approval of their partnered anti-HER2 antibody-drug conjugate earlier this year, AstraZeneca and Daiichi Sankyo are riding high on the promise of their blooming partnership. Now a second ADC is showing promise in hard-to-treat breast cancer, and the companies have their eyes set on their only approved competitor in the space. AstraZeneca and Daiichi Sankyo’s next-gen ADC datopotamab deruxtecan posted a 43% response rate and five confirmed complete or partial responses among 21 patients with triple-negative breast cancer, according to cohort data from the TROPION-PanTumor01 Phase I study presented Saturday at the virtual ESMO Breast annual meeting. The vast majority of those patients were treated with 6-mg doses of the drug while two received an 8-mg high dose. On top of the five confirmed responses, the partners were awaiting confirmation on four additional responses at the Jan. 8 cutoff date. Datopotamab posted a disease control rate of 95%. It’s early days, but the data stack up well in terms of ORR against Gilead and immunomedics’ Trodelvy, the first TROP2-targeted ADC approved for TNBC in April. AstraZeneca opted in June to shell out $1 billion upfront for co-development rights to datopotamab, a follow-up on its winning partnership with Daiichi on anti-HER2 drug Enhertu. The partners added the TNBC cohort after uncorking early data at last year’s ASCO showing datopotamab posted a 38% ORR in 34 advanced non-small cell lung cancer patients at an 8-mg high dose. Among all tested doses, the drug hit a 25% ORR. As of a Sept. 4 update, datopotamab posted an ORR ranging from 21% to 25%, as assessed by an independent central review, among 159 patients in that study. TNBC is a tough-to-treat indication with a particularly poor prognosis, with patients in the AstraZeneca study having undergone a median four prior lines of treatment and up to nine lines of treatment. Thirty-three percent of patients posted a Grade 3 side effect or higher with stomatitis, fatigue and anemia reported as the most common. Meanwhile, none of those serious events were diarrhea or neutropenia — a concern given both Trodelvy and Enhertu’s labels. Cristian Massacesi Meanwhile, the TNBC cohort reported zero cases of interstitial lung disease, a big safety red flag that cropped up in the NSCLC arm of the datapotamab study and is listed a black box warning on Enhertu’s label. Both TROP2 and HER2 are expressed on a range of tumor types, but also on healthy cells in the lungs, which can lead to off-target toxicities. Eight cases of ILD were reported in the NSCLC arm of TROPION-PanTumor01, with six reports and one death in the 8-milligram arm. All but one of those cases were deemed to be treatment related. Daiichi and now AstraZeneca have argued that datopotamab could have best-in-class efficacy and safety with a lower drug-to-antibody ratio and a more stable linker. Toxicity is a big concern for the ADC class on the whole, with Pfizer abandoning its own anti-TROP2 drug, PF-06664178, back in 2016. “What we believe at AstraZeneca and through our relationship Daichii Sankyo is we can be a premier company in the ADC space,” Cristian Massacesi, AstraZeneca’s senior VP and head of late stage development oncology, told Endpoints News. “Enhertu and (datopotamab) I believe are best-in-class agents. Even though there’s a backbone of chemotherapy in breast cancer, this is a much better way to deliver chemotherapy. The key question is, how good is your drug?”