Antibody-Drug Conjugates, TKIs Drive Improved Outcomes in HER2+ Breast Cancer

Joanne Mortimer, MD

The practice-changing treatment regimens that were evaluated in the pivotal KATHERINE, HER2CLIMB, and DESTINY-Breast01 trials in women with HER2-positive breast cancer are pushing the needle forward in making this breast cancer subtype a chronic disease, according to Joanne Mortimer, MD.

“When the CLEOPATRA update was presented, 37% of women with metastatic HER2-positive breast cancer were still alive at 8 years, demonstrating what a chronic disease this is. That number was before the availability of tucatinib [Tukysa] and trastuzumab deruxtecan [fam-trastuzumab deruxtecan-nxki (Enhertu)], so this truly is a chronic disease,” said Mortimer, associate director for Education and Training at the Comprehensive Cancer Center, vice chair and professor in the Department of Medical Oncology and Therapeutics Research, City of Hope, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on breast cancer. 

Patients with locally advanced breast cancer that is greater than 2 cm and/or who have axillary lymph node involvement should be treated with chemotherapy plus trastuzumab (Herceptin) and pertuzumab (Perjeta) followed by surgery, said Mortimer, who is also director of the Women’s Cancer Programs at City of Hope. Patients with residual disease after surgery should receive ado-trastuzumab emtansine (T-DM1; Kadcyla) for 14 cycles, irrespective of hormone receptor positivity, based on findings from the KATHERINE trial.

The phase 3 study enrolled patients with residual invasive locally advanced HER2-positive breast cancer who had received a minimum of 6 cycles of neoadjuvant therapy, including a minimum of 9 weeks of a taxane and trastuzumab. Patients were randomized to 3.6 mg/kg of T-DM1 or 6 mg/kg of trastuzumab every 3 weeks for 14 cycles within 12 weeks of surgery.

Patient characteristics were well balanced between arms, said Mortimer. She added that approximately 75% of patients in both arms had received a prior anthracycline, which could have been due to costal differences, and approximately 20% of patients in both arms received trastuzumab plus pertuzumab.

At a median follow-up of 41.1 months, the primary end point of invasive disease-free survival (iDFS) was maintained, said Mortimer. The 3-year iDFS rate was 88.3% with T-DM1 versus 77.0% with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P < .001).¹ The 3-year freedom from distant recurrence was 89.7% and 83.0%, respectively (HR, 0.60; 95% CI, 0.45-0.79).

“The study was powered to show a 6% difference in iDFS, and with a median follow-up of 41.1 months, there is an 11% difference in iDFS, far exceeding the expectations of the study,” said Mortimer, who is also the Baum Family Professor in Women’s Cancers at City of Hope.  

For patients with recurrent metastatic HER2-positive disease, tucatinib (Tukysa) should be discussed, said Mortimer, based on findings from the phase 2 HER2CLIMB trial. The pivotal trial enrolled patients with metastatic HER2-positive disease who had received prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients with stable and active brain metastases were eligible for enrollment. 

“[HER2CLIMB] was a very important study because it included 291 women with brain metastases,” said Mortimer. 

The study design was such that patients were randomized 2:1 to 300 mg of tucatinib plus 6 mg/kg of trastuzumab plus 1000 mg/m2 every 14 days of a 21-day cycle or placebo plus trastuzumab plus capecitabine (n = 202) in the same schedule.

The primary end point of progression-free survival (PFS) was met, demonstrating a median PFS of 7.8 months in the tucatinib arm versus 5.6 months in the placebo arm.² The 1-year PFS rates were 33.1% and 12.3%, respectively (HR, 0.54; 95% CI, 0.42-0.71; P < .001). The median OS also favored the tucatinib arm, at 21.9 months versus 17.4 months with placebo (HR, 0.66; 95% CI, 0.50-0.88; P = .005). The 2-year OS rates were 44.9% and 26.6%, respectively.

The objective response rate (ORR) was 40.6% in the tucatinib arm versus 22.8% in the placebo arm.

In terms of toxicity, the major adverse effects (AEs) that were reported were the addition of tucatinib were diarrhea, palmar-plantar erythrodysesthesia syndrome, and nausea, said Mortimer, who added that transaminase elevations are also more commonly seen with tucatinib.

In patients with brain metastases, the median central nervous system (CNS)-PFS was 9.9 months with tucatinib versus 4.2 months with placebo (HR, 0.32; 95% CI, 0.22-0.48; P < .00001).³ The median overall survival (OS) was 18.1 months and 12.0 months, respectively (HR, 0.58; 95% CI, 0.40-0.85; P = .005).

“The study demonstrated that tucatinib can keep brain metastases under control for a longer period of time [compared with capecitabine and trastuzumab alone],” said Mortimer. “Increasingly, our goal is to prolong the time before we need radiation therapy, and drugs like tucatinib are very important.”

Another agent that has been added to the armamentarium is trastuzumab deruxtecan, based on findings from the phase 2 DESTINY-Breast01 study. The pivotal study enrolled women with unresectable or metastatic HER2-positive breast cancer who had received at least 2 prior therapies in the metastatic setting. 

In the study, 184 women received 5.4 mg/kg of the drug every 3 weeks until disease progression or unacceptable toxicity. Of note, patients had received a median of 6 prior lines of therapy (range, 2-27).

The waterfall plot, which was used to display the primary end point of ORR, “is certainly the envy of every drug developer,” said Mortimer. Of 168 patients who were evaluated for response, only 4 had experienced disease progression, translating to an ORR of 60.9%.⁴ 

“One of the most impressive components of trastuzumab deruxtecan is that the median time to response is 1.6 months,” said Mortimer. 

The median duration response (DOR) was 14.8 months, and the median PFS was 16.4 months. Among the 24 women with brain metastases, the median PFS was 18.1 months, and the median OS was 16.4 months.

“Similar to tucatinib, this looks to be an important drug in keeping brain metastases under control and hopefully prolonging the time to radiation therapy,” said Mortimer.

Updated data, presented during the 2020 San Antonio Breast Cancer Symposium, indicated that, with an additional 9.4 months of follow-up, the median DOR was 20.8 months, and the estimated 12- and 18-month OS rates were 85% (95%, 79%-90%) and 74% (95% CI, 67%-80%), respectively. The median PFS was 19.4 months (95% CI, 14.1 months–not estimable [NE]), and the preliminary median OS, although still immature, was 24.6 months (95% CI, 23.1–NE).⁵

“When you treat patients with this agent, often the tumor marker goes up before it goes down, so just be aware of that, that you don’t always see rapid tumor shrinkage, even though ultimately the patient may response,” cautioned Mortimer. 

Regarding toxicity, the most common AEs were nausea, fatigue, hair loss, and vomiting, although interstitial pneumonitis is the main cause for concern, said Mortimer.

“Interstitial pneumonitis has been the case of death in certain instances, so when you’re treating these patients, you do need to be aware of shortness of breath when it occurs,” concluded Mortimer. 

References

1. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
3. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl):1005. doi:10.1200/JCO.2020.38.15_suppl.1005
4. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Eng J Med. 2020;382(7):601-621. doi:10.1056/NEJMoa1914510
5. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PD3-06. https://bit.ly/3m7rDoV.