ESMO 2023: Antibody-drug Conjugates-Promising Results in the Treatment of Breast Cancer and Beyond

During the annual ESMO 2023 Congress, organized by the European Society for Medical Oncology, held October 20 – 24, 2023 in Madrid, Spain,  antibody-drug conjugates or ADCs took center stage, with presentations demonstrating the potential these ADCs show in the rapidly changing treatment landscape for various cancers.

Especially favorable results from from large randomized clinical trials with multiple ADCs were reported. Among these presentations where results from clinical studied demonstrating that in the treatment of HER2-non-amplified breast cancer and in patients diagnosed with locally recurrent inoperable, or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer, datopotamab deruxtecan, trastuzumab deruxtecan (Enhertu^®; Daiichi Sankyo and AstraZeneca) and sacituzumab govitecan (Trodelvy^®; Gilead) are showing great promise.

Datopotamab deruxtecan takes center stage
A Presidential Symposium highlighted PFS data in heavily pre-treated patients from the TROPION-Lung01 Phase 3 trial evaluating the TROP2-directed ADC datopotamab deruxtecan (also known as Dato-DXd) on pretreated patients with advanced Non-small Cell Lung cancer (NSCLC) with or without actionable genomic alterations.

In July 2023, datopotamab deruxtecan, a specifically engineered TROP2-directed ADC being jointly developed by AstraZeneca and Daiichi Sankyo, became the first ADC to demonstrate a statistically significant improvement in PFS and a trend in improvement for OS compared to docetaxel, the current standard-of-care chemotherapy.

Additionally, a mini-oral presentation featured initial results from the TROPION-Lung05 Phase II trial evaluating datopotamab deruxtecan in patients with heavily pretreated advanced NSCLC with actionable genomic mutations (AGA). There are currently no TROP2-directed antibody drug conjugates approved for the treatment of patients with lung cancer.

TROPION-Breast01
Another Presidential Symposium will showcase data from the TROPION-Breast01 Phase 3  trial of datopotamab deruxtecan in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative breast cancer previously treated with endocrine-based therapy and at least one systemic therapy.

In September 2023, datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in PFS and a trend in improvement for OS compared to investigator’s choice of chemotherapy.

The outcomes of the TROPION-Breast01 trial showed that datopotamab deruxtecan versus investigator’s choice of chemotherapy (6.9 months versus 4.9 months; hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.52–0.76; p<0.0001) in 732 patients with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer who had received previous chemotherapy, met its primary endpoint, significantly improving PFS.

The study confirmed that the PFS benefit was consistent across the studies subgroups studied. Overall survival (OS) rates with the datopotamab deruxtecan group (HR 0.84, 95% CI 0.62–1.14), although the data are not yet mature.

Trastuzumab deruxtecan across HER2-expressing tumors
New data from the DESTINY-PanTumor02 and DESTINY-PanTumor01 Phase II trials underscored the potential of trastuzumab deruxtecan for previously treated patients with HER2-expressing or HER2-mutated advanced solid tumors, respectively, who currently have no targeted treatment options.

A late-breaking mini-oral presentation of primary results from DESTINY-PanTumor02 will highlight efficacy and safety outcomes for trastuzumab deruxtecan in patients with HER2-expressing solid tumors.

In July 2023, high-level primary analysis results showed trastuzumab deruxtecan demonstrated clinically meaningful PFS and OS, as well as provided robust and durable tumor responses across multiple HER2-expressing solid tumors in the trial. Additionally, a poster presentation will share exploratory biomarker analyses of HER2 expression and gene amplification in tissue and baseline plasma ctDNA.

• A further oral presentation featured the first report of primary results from DESTINY-PanTumor01 in patients with solid tumors that have specific HER2-activating mutations.
• A mini-oral presentation feature post-hoc pooled efficacy and safety analyses of the DESTINY-Lung01 and DESTINY-Lung02 Phase II trials of trastuzumab deruxtecan in patients with HER2-mutated metastatic NSCLC with and without brain metastases.
• Several presentations featured new data from the DESTINY-Breast clinical program for trastuzumab deruxtecan, including its efficacy in patients with brain metastases.

DESTINY-Breast04-study
Updated survival data from the DESTINY-Breast04 trial indicate a sustained improvement in Overall Survival (OS).  The data confirmed that after a median follow-up of 32.0 months, median OS was 22.9 months for the 373 patients treated with trastuzumab deruxtecan and 16.8 months for the 184 patients treated with treatment of physician’s choice (TPC; HR 0.69, 95% CI 0.55–0.86).

Furthermore, median PFS was 8.8 months for the trastuzumab deruxtecan arm and 4.2 months for the TPC arm (HR 0.36, 95% CI 0.29–0.45). In the cohort of patients with a hormone receptor-negative tumor, the study results also demonstrated a 42% reduction in the risk of death (HR 0.58, 95% CI 0.31–1.08) and a 71% reduction in the risk of disease progression or death (HR 0.29, 95% CI 0.15–0.57) with trastuzumab deruxtecan compared to TPC.

Robust and durable
“The progression-free survival and overall survival results for trastuzumab deruxtecan alongside the continued robust and durable tumor responses seen with further follow up underscore the potential value of this important medicine for patients with HER2-expressing cancers who currently have no targeted treatment options,” noted Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca.

“With a high unmet need in these cancers, we are working with health authorities to bring trastuzumab deruxtecan to patients with HER2-expressing cancers that could potentially benefit from this medicine as quickly as possible,” he added.

“These updated results from the DESTINY-PanTumor02 trial are important as we work to reshape the clinical landscape in HER2-expressing advanced cancers, where patients currently have limited treatment options and face a poor prognosis,” explained Mark Rutstein, Global Head, Oncology Development, Daiichi Sankyo.

“The overall survival demonstrated by trastuzumab deruxtecan in these patients is a significant step forward in the potential to advance current standards of care and offer new options for patients with HER2-expressing cancers,” Rutstein further noted.

The positive outcomes of the trials presented during the ESMO 2023 Congress confirm that in the treatment of metastatic cancer lacking HER2 amplification, ADCs are proving to be more effective when compared to conventional, standard of care chemotherapy.

Similar results where reported in the New England Journal of Medicine (NEJM) showing that in the treatment of patients with HER2-low metastatic breast cancer trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy.[1]

Sacituzumab govitecan
An unrelated study with sacituzumab govitecan (Trodelvy^®; Gilead), an ADC with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer, also demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.[2]

Data for sacituzumab govitecan across a range of difficult-to-treat solid tumors include real-world data that reinforce sacituzumab govitecan as a standard-of-care option in second-line metastatic Triple-negative Breast Cancer (TNBC), a clinically aggressive disease associated with poor prognosis with a median overall survival (OS) after metastasis of 15.5 months, and new post-hoc efficacy analyses from the Phase 3 TROPiCS-02 study in pre-treated HR+/HER2- metastatic breast cancer.

• Two mini-oral presentations from the TROPiCS-03 basket trial supported the potential of sacituzumab govitecan in extensive-stage small cell lung cancer (ES-SCLC) and advanced head and neck squamous cell carcinoma (HNSCC). Preliminary findings from a clinical collaboration with Dana-Farber Cancer Institute in 2L metastatic urothelial cancer, demonstrated for the first time in any tumor, that potentially two ADCs can be given in combination together.

“[The Data we’ve presented] at ESMO 2023 reflects a broad clinical development program in difficult-to-treat cancers,” said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology.

“Sacituzumab govitecan has the potential to impact many patients with cancer across multiple indications, as demonstrated by [these] presentations featuring new data in extensive-stage small cell lung cancer, metastatic urothelial cancer and previously treated head and neck cancer, along with new analyses in metastatic breast cancer,” Grossman added.

Next steps
ESMO 2023 Congress attendees were especially encourage to see that the study results for the safety profile of datopotamab deruxtecan showed that only 2/360 participating patients experienced grade ≥3 drug-related interstitial lung disease (ILD) and that, compared with chemotherapy, grade ≥3 treatment-related adverse events observed compared (21% vs 45%) where lower.

However, with positive outcomes of theses studies, physicians are now looking for additional data to help guide them in selecting which ADC to administer to a given patient and whether any are effective after disease progression.

ESMO 2023 Congress Abstracts

Clinical trials
First-in-human Study of DS-1062a for Advanced Solid Tumors (TROPION-PanTumor01) – NCT03401385
Study of DS-1062a Versus Docetaxel in Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer With or Without Actionable Genomic Alterations (TROPION-LUNG01) – NCT04656652
A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator’s Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)
NCT05104866
Study of DS-1062a in Advanced or Metastatic Non-small Cell Lung Cancer With Actionable Genomic Alterations (TROPION-Lung05) – NCT04484142
A Study of Novel Anti-cancer Agents in Patients With Metastatic Triple Negative Breast Cancer (BEGONIA) – NCT03742102
A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1) – NCT03248492
DS-8201a in Pre-treated HER2 Breast Cancer That Cannot be Surgically Removed or Has Spread [DESTINY-Breast02] – NCT03523585
DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/​or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03] – NCT03529110
Trastuzumab Deruxtecan (DS-8201a) Versus Investigator’s Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04] – NCT03734029
A Phase 2 Study of T-DXd in Patients With Selected HER2 Expressing Tumors (DPT02) – NCT04482309
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/​HER2- Metastatic Breast Cancer (TROPiCS-02) – NCT03901339
Trial of Sacituzumab Govitecan in Participants With Refractory/​Relapsed Metastatic Triple-Negative Breast Cancer (TNBC) (ASCENT) NCT02574455

Highlights of prescription information
Trastuzumab deruxtecan (Enhertu^®; Daiichi Sankyo/AstraZeneca) [Prescribing Information]
Sacituzumab govitecan (Trodelvy^®; Gilead)[Prescribing Information]

References
[1] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.
[2] Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. doi: 10.1200/JCO.22.01002. Epub 2022 Aug 26. PMID: 36027558.

Featured image: ESMO 2017. Photo courtesy: 2017 – 2023 European Society for Medical Oncology. Used with permission.

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