Updated results from the BEGONIA phase 1b/2 trial for the cohort of patients treated with datopotamab deruxtecan + durvalumab (Imfinzi®; AstraZeneca;  Arm 7) showed that the treatment combination demonstrated durable tumor responses without  new safety signals in patients with previously untreated advanced or metastatic triple negative breast cancer (mTNBC) with six months additional follow-up from the previous data cut-off.

These results were presented today during a mini oral session (379MO) at the European Society for Medical Oncology (ESMO 2023 Congress, held in Madrid, Spain, October 20 – 24, 2023.

The BEGONIA trials is an open-label, two-part, multicenter phase 1b/2 trial evaluating durvalumab in combination with oncology therapies with or without paclitaxel for the first-line treatment of metastatic TNBC.

Arm 7 of the trial is evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in combination with durvalumab in patients with previously untreated, unresectable locally advanced or metastatic TNBC. The primary endpoints in this study are safety and tolerability. Secondary endpoints are investigator-assessed ORR, PFS and DoR.

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Enrollment is currently underway for Arm 8 of the BEGONIA trial, which is evaluating datopotamab deruxtecan plus durvalumab in patients with TNBC whose tumors have high levels of PD-L1 expression.

Datopotamab deruxtecan
Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody-drug conjugate or ADC being jointly developed by Daiichi Sankyo and AstraZeneca. The investigational agent is comprised of a humanized anti-TROP2 IgG1 monoclonal
antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Triple negative breast cancer
Breast cancer is the most common cancer in the world and leading cause of cancer-related death. More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.

While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.

Approximately 300,000 people worldwide are diagnosed annually with TNBC, the most aggressive breast cancer subtype. [1][2[3]] Less than half of patients with metastatic TNBC respond to current first-line treatment options which can include chemotherapy alone or in combination with an immunotherapy. [3[4][5]

Among patients with tumors that respond to initial treatment, disease progression is common and rapid, often occurring within two years.[3][5][6][7]

Results showed that datopotamab deruxtecan plus durvalumab, an anti PD-L1 therapy, demonstrated a confirmed objective response rate (ORR) of 79% (95% confidence interval [CI]: 67-88) including six complete responses (CRs) and 43 partial responses (PRs). Responses were observed regardless of PD-L1 expression level. Median progression-free survival (PFS) was 13.8 months (95% CI: 11-not calculable [NC]) and median duration of response (DoR) was 15.5 months (95% CI: 9.9-NC) with 11.7 months of follow-up.

“These results for datopotamab deruxtecan plus durvalumab in the first-line triple negative breast cancer setting are highly encouraging, particularly the 79% objective response rate,” noted Peter Schmid, MD, Barts Cancer Institute, London, United Kingdom, and investigator in the trial.

“This magnitude of response is especially notable given the majority of patients in this cohort have PD-L1 low tumors, representing a population for whom treatment has long been limited to standard chemotherapy,” Schmid added.

Safety profile
The safety profile of datopotamab deruxtecan in combination with durvalumab was consistent with the known safety profiles of both agents. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 57% of patients. The most common grade 3 or higher TEAEs were increased amylase (18%), stomatitis (11%), constipation (2%), fatigue (2%), vomiting (2%) and decreased appetite (2%). There were three interstitial lung disease (ILD) events adjudicated as drug-related by an independent committee
including two grade 2 events and one grade 1 event.

“Disease progression after initial treatment is a reality for patients with triple negative breast cancer, underscoring the need for more durable treatment options,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo.

“These findings showcase the potential of datopotamab deruxtecan in previously untreated advanced triple negative breast cancer and, following the positive results of our TROPION-Breast01 phase 3 trial, build on the growing body of evidence for the potential use of this TROP2 directed antibody drug conjugate, alone and in combinations, in several subtypes of breast cancer,” Rutstein further explained.

“Progress in the first-line advanced triple negative breast cancer setting has been modest for years and new therapeutic strategies are needed to improve outcomes for patients with this aggressive breast cancer subtype,” said Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca.

“These updated results from the BEGONIA trial reinforce our confidence in the potential for
datopotamab deruxtecan to become a new, important treatment modality in this setting as we eagerly await results from our ongoing phase 3 triple negative breast cancer program,” Massacesi explained.

Arm 7
In Arm 7 of the BEGONIA trial (n=62), the majority of patients (n=54) had tumors with low PD-L1 expression (tumor area positivity [TAP]<10%). Seven patients had tumors with high PD-L1 expression (TAP≥10%). As of the February 2, 2023 data cut-off, 29 patients (47%) remained on study treatment.

Drug development
Daiichi Sankyo and AstraZeneca have two phase 3 trials evaluating datopotamab deruxtecan in patients with TNBC.

  • TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD1/PD-L1 therapy.
  • TROPION-Breast03 is evaluating datopotamab deruxtecan with and without durvalumab
    versus investigator’s choice of therapy in patients with stage 1 to 3 TNBC with residual disease after neoadjuvant therapy.

During the ESMO 2023 Congress in Madrid, several presentations demonstrated showcasing the strength and depth of data for datopotamab deruxtecan across multiple tumor types and settings, including results from the TROPION-Lung01 and TROPION-Breast01 phase 3 trials.

Clinical trials
A Study of Novel Anti-cancer Agents in Patients With Metastatic Triple Negative Breast Cancer (BEGONIA) – ClinicalTrials.gov Identifier: NCT03742102
A Study of Dato-DXd Versus Investigator’s Choice Chemotherapy in Patients With Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer, Who Are Not Candidates for PD-1/PD-L1 Inhibitor Therapy (TROPION-Breast02) – ClinicalTrials.gov Identifier: NCT05374512
A Study of Dato-DXd With or Without Durvalumab Versus Investigator’s Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Without Pathological Complete Response Following Neoadjuvant Therapy (TROPION-Breast03) – ClinicalTrials.gov Identifier: NCT05629585

Highlights of Prescribing Information
Durvalumab (Imfinzi®; AstraZeneca)[Prescribing Information]

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Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

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