ADC Developments in HER2– Breast Cancer Treatment Shake Up Paradigm

As additional antibody-drug conjugates continue to emerge for the treatment of patients with HER2-negative breast cancer, identifying optimal sequencing strategies and managing toxicities associated with these agents remain top priorities for their use, according to Hope S. Rugo, MD.

As additional antibody-drug conjugates (ADCs) continue to emerge for the treatment of patients with HER2-negative breast cancer, identifying optimal sequencing strategies and managing toxicities associated with these agents remain top priorities for their use, according to Hope S. Rugo, MD.

“ADCs [are an] exciting and effective drug delivery system [with] an established role in all of the subsets, plus a new subset [with HER2-low], of breast cancer in the metastatic setting. [They have] huge potential in early-stage disease, and I think that ADCs are likely to replace giving naked chemotherapy in the not-too-distant future,” Rugo said in a presentation at the 40th Annual Miami Breast Cancer Conference. “Toxicity management is critical as we treat our patients with these highly effective, new drugs.”

In her presentation, Rugo, a professor of medicine in the Division of Hematology and Oncology, director of Breast Oncology, and director of Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, detailed key findings and FDA approvals for fam-trastuzumab deruxtecan-nxki (Enhertu) and sacituzumab govitecan-hziy (Trodelvy) across the varying HER2-negative metastatic breast cancer subsets and highlighted other ADCs in the pipeline.

The Landing of Trastuzumab Deruxtecan

Trastuzumab deruxtecan was granted regular approval by the FDA in May 2022 for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and developed disease recurrence during or within 6 months of therapy completion.2 The ADC previously received accelerated approval in December 2019 for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.3

Then, in August 2022, the regulatory agency approved the ADC for the treatment of patients with unresectable or metastatic HER2-low breast cancer, based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029). This showed that trastuzumab deruxtecan demonstrated improvements in progression-free survival (PFS) and overall survival (OS) vs physician's choice of chemotherapy in this patient population.4,5

DESTINY-Breast04 enrolled patients with HER2-low unresectable and/or metastatic breast cancer who received 1 to 2 prior lines of chemotherapy in the metastatic setting or experienced recurrence no more than 6 months after adjuvant therapy. At least 1 prior line of endocrine therapy was required for patients with hormone receptor–positive disease. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization (ISH) negative. Patients were randomly assigned 2:1 to received 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 373) or physician’s choice of chemotherapy (n = 184).

The median PFS for the overall treated population was 9.9 months (95% CI, 9.0-11.3) for trastuzumab deruxtecan and 5.1 months (95% CI, 4.2-6.8) for physician’s choice of chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P < .001). The median OS for the overall population was 23.4 months (95% CI, 20.0-24.8) for the trastuzumab deruxtecan arm and 16.8 months (95% CI, 14.5-20.0) in the physician’s choice arm (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

Patients with hormone receptor–positive disease treated with trastuzumab deruxtecan (n = 331) experienced a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for those given chemotherapy (n = 163; HR, 0.51; 95% CI, 0.40-0.64; P < .001). This subset achieved a median OS of 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2 to 22.4) with chemotherapy (HR, 0.64; 95% CI, 0.48-0.86; P = .003).

Among patients with hormone receptor–negative breast cancer, those treated with trastuzumab deruxtecan (n = 40) experienced a median PFS of 8.5 months (95% CI, 4.3-11.7) vs 2.9 months (95% CI, 1.4-5.1) for those in the physician’s choice group (n = 18; HR, 0.46; 95% CI, 0.24-0.89). The median OS was 18.2 months (95% CI, 13.6–not evaluable) in the trastuzumab deruxtecan arm and 8.3 months (95% CI, 5.6-20.6) in the physician’s choice arm (HR, 0.48; 95% CI, 0.24-0.95).

The clinical benefit with the ADC was also observed across various patient subgroups, including in those with baseline central nervous system–controlled metastases.6

Regarding safety, she noted that nausea is the most common toxicity with trastuzumab deruxtecan, and this does require prophylaxis. She added that treatment with olanzapine (Zyprexa) before bedtime is effective at managing the nausea, which Rugo added is rarely observed at higher grades.

Drug-related interstitial lung disease (ILD) or pneumonitis was also reported in 12.1% of patients in the trastuzumab deruxtecan arm, including 3 patients (0.8%) who had grade 5 ILD/pneumonitis.

An article in ESMO Open explored risk factors for ILD, which included Japanese ethnicity, decreased renal function and worse lung function at start of treatment, among others.7

“And we don't use the higher dose [of trastuzumab deruxtecan in these patients],” Rugo explained. “Eighty-seven percent [of ILD/pneumonitis] occurred within the first 12 months of the first dose. [However], that doesn't mean that [patients] can't die from ILD in 2 years, because we have seen late fatal cases—so you don't want to let your guard down.”

In an analysis of the concordance between previously determined HER2 scores and central HER2 scores, as well as tumor sample characteristics for patients screened and enrolled in DESTINY-Breast04, 22% of patients had discordant samples (n = 237/1060). Eighty-eight percent (n = 208/237) of those patients were centrally scored as IHC 0, and 12% were IHC 2+/ISH+ or IHC 3+.8

The ongoing phase 3 DESTINY-Breast06 trial (NCT04494425) is examining the ADC vs physician’s choice of chemotherapy in patients with hormone receptor–positive, HER2-low (defined as IHC 2+/ISH– and IHC 1+) or HER2 IHC >0/<1+ metastatic breast cancer. Data from this study are expected within the next year, Rugo said.

Results from the phase 2 DEBBRAH trial (NCT04420598) have pointed to the potential for trastuzumab deruxtecan in patients with HER2-positive or HER2-low breast cancer with brain metastases.9 In patients with HER2-low disease with asymptomatic brain metastases in cohort 2 (n = 6) and those with HER2-low disease with progressing brain metastases after local treatment in cohort 4 (n = 6), the intracranial overall response rates (IC-ORRs) were 66.7 and 33.3%, respectively, with all responders achieving a partial response, and no patients having progressive disease. Across both groups, the ORR was 41.7% with a clinical benefit rate of 50.0%.

Other research efforts are exploring the combination of trastuzumab deruxtecan with immunotherapy. In the phase 1/2 BEGONIA trial (NCT03742102), patients with HER2-low metastatic triple-negative breast cancer (TNBC; n = 58) who were treated with the ADC plus durvalumab (Imfinzi) experienced an ORR of 56.9% and a median PFS of 12.6 months (95% CI, 8.3–not calculated).10

However, 8 instances of adjudicated ILD were reported, and 2 more were pending review. “I think the problem with combining these drugs is that you can't figure out what drug is causing the ILD and which one to stop,” Rugo said. “So, it's quite complicated, and [this] isn't being pursued in the TNBC population right now.”

Sacituzumab Govitecan Arrives on the Scene

In April 2022, the FDA approved sacituzumab govitecan for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.11 Additionally, in February 2023, the regulatory agency approved the ADC for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.12

The approval in hormone receptor–positive, HER2-negative disease was supported by data from the phase 3 TROPiCS-02 trial (NCT03901339), where patients were randomized 1:1 to 10 mg/kg of sacituzumab govitecan on days 1 and 8 of every 21-day cycle (n = 272) or physician’s choice of chemotherapy (n = 271).13

The ADC elicited a median PFS of 5.5 months (95% CI, 4.2-7.0) compared with 4.0 months (95% CI, 3.1-4.4) for chemotherapy (stratified HR, 0.66; 95% CI, 0.53-0.83; stratified log-rank P = .0003). Patients treated with sacituzumab govitecan experienced a median OS of 14.4 months (95% CI, 13.0-15.7) vs 11.2 months (95% CI, 10.1-12.7) for chemotherapy (stratified HR, 0.79; 95% CI, 0.65-0.96; stratified log-rank P = .02).

Trop-2 was found in 95% of tumor samples taken from patients enrolled in TROPiCS-02, and 58% of patients had an H score of at least 100. There was no correlation between Trop-2 expression on response or safety, Rugo noted.

She also highlighted other clinical trials evaluating sacituzumab govitecan in other settings for patients with TNBC or hormone receptor–positive breast cancer. ASCENT-03 (NCT0538229) is investigating the ADC vs physician’s choice of chemotherapy as first-line therapy for patients with PD-L1–negative TNBC, and the phase 3 ASCENT-04 trial (NCT05382286) is looking at the agent plus pembrolizumab (Keytruda) vs chemotherapy plus the PD-1 inhibitor in first-line PD-L1–positive TNBC. The phase 3 ASCENT-07 trial, set to be initiated in 2023, will examine sacituzumab govitecan vs chemotherapy in first-line hormone receptor–positive/HER2-negative locally advanced, unresectable or metastatic breast cancer.

More ADCs Plow Through Pipeline

Datopotamab deruxtecan (Dato-DXd) is another Trop-2–targeted ADC that features a Trop-2 IgG1 monoclonal antibody with a topoisomerase I inhibitor payload and a tetrapeptide-based cleavable linker. The phase 1 TROPION-PanTumor01 trial (NCT03401385) investigated the ADC in patients with metastatic TNBC or hormone receptor–positive, HER2-negative metastatic breast cancer who have progressed on at least 1 endocrine therapy and were previously treated with 1 to 3 lines of chemotherapy in the advanced setting.14

All patients with TNBC or hormone receptor–positive/HER2-negative disease experienced an ORR of 32% per blinded independent central review and a median PFS of 4.4 to 7.3 months. In patients who were naïve to treatment with a topoisomerase I inhibitor, the ORR was 44%.

Notably, 73% to 83% of patients experienced any-grade stomatitis, including grade 3 in 10% of patients. “[Datopotamab deruxtecan has the] same toxin as trastuzumab deruxtecan [and] a similar antibody target to sacituzumab, [yet stomatitis was] a new toxicity,” Rugo said. “Clearly toxicity is determined by both the antibody and the toxin.”

BEGONIA also evaluated the addition of durvalumab to datopotamab deruxtecan as first-line treatment for patients with metastatic TNBC. Among 53 evaluable patients, the combination elicited an ORR of 73.6%, and 82% of responses were ongoing at data cutoff.15 Notably, responses were observed in patients with PD-L1–low and PD-L1–high tumors. Updated data showed that any-grade stomatitis occurred in 55.7% of patients.

“[Stomatitis] can be managed with this steroid mouthwash that we piloted with everolimus [Afinitor] in the [phase 2] SWISH trial [NCT02069093], which seems to remarkably decrease the incidence and severity of stomatitis with this drug,” Rugo explained.

The phase 3 TROPION-Breast01 trial (NCT05104866) is evaluating datopotamab deruxtecan vs chemotherapy as second- or third-line treatment for patients with hormone receptor–positive/HER2-negative breast cancer. Additionally, datopotamab deruxtecan is under investigation vs chemotherapy as first-line treatment for patients with PD-L1–negative TNBC in the phase 3 TROPION-Breast02 trial (NCT05374512).

Furthermore, the HER3-targeted ADC patritumab deruxtecan elicited responses in a phase 1/2 trial (NCT02980341) in heavily pretreated patients with HER3-expressing metastatic breast cancer. Patients with hormone receptor–positive/HER2-negative, HER2-positive, and TNBC experienced ORRs of 30%, 23%, and 43%, respectively.16 The median PFS for these patients was 7.2 months, 5.9 months, and 8.3 months, respectively.

References

  1. Rugo HS. Antibody-drug conjugates for HER2-negative breast cancer in clinical practice. Presented at: 40th Annual Miami Breast Cancer Conference; March 2-5, 2023; Miami Beach, FL.
  2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed March 3, 2023. https://www.fda.gov/drugs/
  3. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. News release. FDA. December 20, 2019. Accessed March 3, 2023. https://www.fda.gov/news-events/
  4. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed March 3, 2023. https://www.fda.gov/news-events/
  5. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
  6. Harbeck N, Modi S, Jacot W, et al. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: subgroup analyses from DESTINY-Breast04. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
  7. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554
  8. Prat A, Modi S, Tsurutani J, et al. Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract HER2-18.
  9. Pérez-García JM, Batista MV, Cortez-Castedo P, et al. Trastuzumab deruxtecan in patients with unstable central nervous system involvement from HER2-low advanced breast cancer: the DEBBRAH trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD7-02.
  10. Schmid P, Wysocki P, Park YH, et al. Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD11-08.
  11. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. News release. FDA. April 7, 2021. Accessed March 3, 2023. https://www.fda.gov/drugs/
  12. US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences. February 3, 2023. Accessed March 3, 2023. https://www.gilead.com/news-and-press/
  13. Rugo HS Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376. doi:10.1200/JCO.22.0100Pantumor 01
  14. Meric-Bernstem F, Krop IE, Juric D, et al. Phase 1 TROPION-PanTumor01 study evaluating datopotamab deruxtecan (Dato-DXd) in unresectable or metastatic hormone receptor–positive/HER2–negative breast cancer (BC). Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD13-08.
  15. Schmid P, Wysocki P, Ma C, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD11-09.
  16. Krop IE, Masuda N, Mukohara T, et al. Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC). J Clin Oncol. 2022;40(suppl 16):1002. doi:10.1200/JCO.2022.40.16_suppl.1002