Novel Antibody-Drug Conjugates Show Encouraging Activity in TNBC

Aditya Bardia, MD, MPH

Novel antibody-drug conjugates (ADCs) have demonstrated high response rates in patients with heavily pretreated metastatic breast cancer, and ongoing studies targeting actionable cell-surface markers may further expand their clinical utility, according to Aditya Bardia, MD, MPH.

There are several ADCs in development that target cell-surface markers in triple-negative breast cancer (TNBC), namely TROP-2, LIV1, HER2, and HER3. These ADCs consist of a high-affinity antibody linked with a toxic payload. They bind to the target antigen and are internalized by the cell, where the linker is degraded by the lysosome to release the cytotoxic payload within the cancer cell, causing apoptosis.

“The question is how can we further improve the response rates,” explained Bardia, director of Precision Medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic, Massachusetts General Hospital Cancer Center, and assistant professor of medicine, Harvard Medical School. “We saw a response rate of 30% to 40% with these antibody-drug conjugates, can we improve that to 50%, 60%, 70%, 80% and further improve the outcomes of patients with metastatic breast cancer.”

Sacituzumab Govitecan

Sacituzumab govitecan targets TROP-2 to release SN-38, the active metabolite of irinotecan. In a phase I/II single-arm open-label study,¹ Bardia along with other researchers, found that sacituzumab govitecan showed durable objective responses in pretreated patients with metastatic TNBC, with myelotoxicity being the major adverse effect.

The study included 108 patients with TNBC. A majority of patients had visceral metastases (80%) and the median time from metastatic diagnosis to treatment in the study was 1.5 years. Sacituzumab govitecan was administered at 10 mg/kg on days 1 and 8 of each 28-day cycle. Overall, 57 patients had moderate (2+) to strong (3+) TROP-2 expression by immunohistochemistry and 5 had weak or absent staining for the marker. The data were not available for the remaining patients.

In results that were published in the New England Journal of Medicine,¹ at a median follow-up of 9.7 months, the objective response rate (ORR) was 33.3% by local assessment (95% CI, 24.6%-43.1%) with a median duration of response (DOR) of 7.7 months (95% CI, 4.9-10.8). The clinical benefit rate (ORR plus stable disease) was 45.4%. By blinded independent central review, the ORR was 34.3% (95% CI, 25.4%-44.0%) and the median DOR was 9.1 months (95% CI, 4.6-11.3).

The median progression-free survival (PFS) was 5.5 months (95% CI, 4.1-6.3). The estimated 6-month PFS rate was 41.9%. By 12 months, the PFS rate with sacituzumab govitecan was estimated at 15.1%. The median overall survival (OS) was 13.0 months (95% CI, 11.2-13.7), with an estimated 6-month OS rate of 78.5% and a 12-month estimate of 51.3%.

Based on these findings, in December 2019 the FDA accepted a biologics license application (BLA) for sacituzumab govitecan as a treatment for patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.

The phase III ASCENT trial (NCT02574455) is currently exploring sacituzumab govitecan in comparison with treatment of physician choice for patients with metastatic TNBC. The trial, which has fully accrued 529 patients, is expected to report results in 2020 (NCT02574455). The current BLA for sacituzumab govitecan, if approved, will provide an accelerated approval for the medication. Findings from the ASCENT trial will act as confirmation.

Ladiratuzumab Vedotin

The ADC ladiratuzumab vedotin (SGN-LIV1A) consist of an anti—LIV-1 antibody connected to a microtubule disrupting agent via a protease-cleavable linker. In phase I findings presented at the 2017 San Antonio Breast Cancer Symposium (SABCS),² the ORR was 25% (15 of 60 patients). The median PFS was 11.0 weeks (6.1-12.1) and the median duration of response was 13.3 weeks (95% CI, 5.3-19.1).

The drug is being evaluated in an ongoing phase I study in patients with metastatic TNBC who have received ≥2 cytotoxic regimens in the unresectable, locally advanced, or metastatic setting (NCT01969643).

At the 2019 SABCS, findings were presented from a phase Ib/II study for the combination of ladiratuzumab vedotin with the PD-1 inhibitor pembrolizumab (Keytruda) in patients with locally advanced or metastatic TNBC.³ According to the abstract, among 26 assessable patients, the ORR was 54% with the combination (95% CI, 33.4%-73.4%). Bardia noted that a majority of patients (>90%) treated with the combination experienced some level of decline in tumor size.

The combination of ladiratuzumab vedotin continues to be assessed in a phase I/II study. The enrollment goal for the study is 97 patients and the estimated completion date is set for May 2020 (NCT03310957).

[Fam-] Trastuzumab Deruxtecan

[Fam-] trastuzumab deruxtecan-nxki (Enhertu), is a novel ADC comprised of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivative; and a tetrapeptide-based cleavable linker.

Bardia noted that the novel HER2-targeting agent has been evaluated in multiple studies. In December 2019, the agent was FDA-approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

The approval was based on findings from the phase II DESTINY-Breast01 trial (NCT03248492).⁴ In the study, trastuzumab deruxtecan induced a confirmed ORR of 60.3% per independent central review (95% CI, 52.9%-67.4%), including a 4.3% complete response rate and a 56% partial response rate. ORRs were consistent across subgroups, including those with prior treatment with pertuzumab (Perjeta) and those with ≥3 prior regimens.

Sixty-seven patients had stable disease (36.4%) and 3 developed progressive disease (1.6%). Two patients were not evaluable. Median duration of response (DOR) was 14.8 months (95% CI, 13.8-16.9) with [Fam-] trastuzumab deruxtecan-nxki, and the disease control rate (DCR) was 97.3% (95% CI, 93.8%-99.1%). The median time to response was 1.6 months (95% CI, 1.4-2.6).

After a median follow-up of 11.1 months (range, 0.7-19.9), median PFS was 16.4 months (95% CI, 12.7-not evaluable [NE]). Median PFS in 24 patients with brain metastases at baseline was 18.1 months (95% CI, 6.7-18.1). Median overall survival was not reached (95% CI, NE-NE).

U3-1402

HER3 overexpression in breast cancer is associated with decreased survival and there are currently no approved HER3-targeted therapies, making it a target of extreme interest. To that end, Bardia noted that an ongoing phase I/II study (NCT02980341) is exploring the safety and efficacy of the investigational ADC U3-1402 in patients with HER3-overexpressing breast cancer.⁵

At a median follow-up of 10.5 months for 42 patients, the ORR with U3-1402 was 42.9% across doses. This included an ORR of 40% for patients treated at a 4 mg/kg dose and 60% of those treated at a 6.4 mg/kg dose. The DCR was 90.5%, which was comprised of a DCR of 86.7% at the 4 mg/kg dose and 100% at the 6.4 mg/kg dose. Further, the DOR was not reached in any arm and the median PFS across doses was 8.3 months (range, 1.2-15.8).⁵

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References

1. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Eng J Med. 2019;380:741-751. doi: 10.1056/NEJMoa1814213.
2. Modi S, Pusztal L, Forero A, et al. Phase 1 study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily pretreated triple-negative metastatic breast cancer. Poster presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Poster PD3-14.
3. Han H, Diab S, Alemany C, et al. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer. December 10-14, 2019; San Antonio, Texas. Poster PD1-06.
4. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi: 10.1056/NEJMoa1914510.
5. Yonemori K, Masuda N, Takahashi S, et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial. Ann Oncol. 2019;30(suppl 3): iii47-iii64. doi: 10.1093/annonc/mdz100.