Relevant Trials Show Which Treatments Are Worth Using in HER2-Positive Breast Cancer

Ruta D. Rao, MD

During a Targeted Oncology Case-Based Peer Perspectives Roundtable event, Ruta D. Rao, MD, associate professor of Medicine, Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, Rush Medical College, Director, Coleman Foundation, Comprehensive Breast Cancer Clinics, and medical director, ay Rush University Cancer Center, discussed the case of 42-year-old woman with HER2-positive breast cancer.

Targeted Oncology^TM: At this point, what are the options for a patient who has residual disease after neoadjuvant therapy?

RAO: [There are] 3 studies in the adjuvant setting. They’re all slightly different.

The ExteNET study [NCT00878709] is the one that looked at neratinib [Nerlynx],¹ and this was after patients had received a year of trastuzumab. This had 2840 patients. The entry criteria [were] stage I to IIIc [disease], but it was later changed to stage II to IIIc. About 24% of the patients were node negative. The majority of patients received anthracyclines and 57% were hormone receptor positive. In terms of invasive disease-free survival [rate] at 5 years, the difference was 90.2% versus 87.7% for patients who received versus did not receive neratinib, and this [had] a hazard ratio of 0.77 [P = .0083].

The APHINITY trial [NCT01358877] was the one that looked at adding pertuzumab in the adjuvant setting.² This was a very large study, 4800 patients, and initially the patients could be node positive or node negative as long as it was greater than a centimeter of tumor, or if they were node negative with less than a centimeter and [had] high-risk factors like age less than 35, grade 3 [disease], or hormone receptor positive. Thirty-four percent of the patients were node negative, 75% received anthracyclines, about two-thirds were hormone receptor positive.

At the 6-year presentation, which we saw at San Antonio in 2019, the 6-year invasive disease-free survival [rate] was 90.6% versus 87.8% [HR, 0.76; 95% CI, 0.64-0.91]. In fact, if you looked at the node-positive patients, the numbers were 87.9% versus 83.4%. There was no difference when you looked at the subset of node-negative patients for the addition of pertuzumab. We had not yet seen an overall survival difference in this study.

The third trial, which we have most recently heard about, is the KATHERINE study [NCT01772472].³ This was a study looking at T-DM1 [trastuzumab emtansine; Kadcyla] in the setting of residual disease after neoadjuvant chemotherapy in 1486 patients. A little more than half were node negative. Again, about threequarters had received anthracyclines, 73% were hormone receptor positive and when you looked that 3-year invasive disease-free survival [rate], there was an 11 [percentage points] absolute difference, or 77.0% versus 88.3% for the patients who received T-DM1.

Just to remind you, these patients with residual disease were randomized to either T-DM1 or trastuzumab after surgery. The hazard ratio here was a 0.5 with a very significant P value [of less than .0001].

Which studies have investigated anthracycline treatment in these patients?

The TRAIN-2 study [NCT01996267] looked at neoadjuvant chemotherapy with or without anthracycline, in the presence of dual HER2 blockade for HER2-positive breast cancer.⁴

This is an open-label randomized phase 3 trial, and they enrolled patients with stage II or III disease and no prior therapy. There were 438 patients, and they were randomized in a 1:1 fashion. They either received 3 cycles of what they called PTC plus pertuzumab, so this is paclitaxel, trastuzumab, and carboplatin plus pertuzumab followed by 6 cycles of the same, so a total of 9 cycles. Or their first 3 cycles were of FEC—5-FU [fluorouracil], epirubicin, and cyclophosphamide—with trastuzumab and pertuzumab, then followed by 6 cycles of the paclitaxel/trastuzumab/ carboplatin with pertuzumab. The primary end point was the pathologic complete response rate.

All these patients received concurrent HP, even the ones getting the anthracycline. With a median follow-up of 49 months, the pathologic complete response rate was 67% for the patients who received anthracycline and 68% for the nonanthracycline, so essentially the same. There was no difference in event-free survival or overall survival for the anthracycline-containing regimen in these patients with stage II and III HER2-positive breast cancer. There was no evidence that these higher risk [patients]—remember these were stage II and III patients—require anthracycline. We know that the addition of anthracycline increases the risk for febrile neutropenia and cardiac toxicity, and hematologic toxicity down the road.

The 3-year event-free survival [rate] was 93.5% and 92.7% for the 2 groups of patients.⁵

I think that just verifies what we’ve all been doing in our practice.

How has the field adapted during the coronavirus disease 2019 (COVID-19) pandemic?

At Rush University Cancer Center, we were doing a lot of neoadjuvant endocrine therapy trying to delay surgery, and then around May or June, we started going back to things as normal. We’re still in that “treating everything as normal” phase right now, I guess waiting to see what happens with hospital beds and capacity at this point. We’ve seen the numbers rise exponentially at Rush, the inpatients as well.

[The use of Phesgo is especially helpful in light of the COVID-19 pandemic]. [The phase 3 FeDeriCa study (NCT03493854) was] the study where they looked at it.⁶ Phesgo is a fixed dose of trastuzumab, pertuzumab, and hyaluronidase that’s given subcutaneously.

In this study, the investigators had 500 patients and they were randomized. Arm A patients received AC [doxorubicin and cyclophosphamide], which could either be given dose dense or every 3 weeks, followed by a taxane of your choice, paclitaxel or docetaxel, but the key was that they received intravenous Herceptin/Perjeta and then went to surgery followed by Herceptin/Perjeta.

Arm B was again AC given either dose dense or every 3 weeks, and then choice of taxane, paclitaxel, or docetaxel, but here, the Herceptin/Perjeta was given as this fixed-dose subcutaneous trastuzumab/pertuzumab along with the taxane, and then they went to surgery followed by the fixed-dose antibody treatment for 42 more weeks.

These were patients with operable or locally advanced breast cancer. They were stage II to IIIc, so again, tumors greater than 2 cm or node positive, what we all agreed was our general criteria for the neoadjuvant patient.

In comparing the pathologic complete response rates between the 2 arms, they’re almost exactly the same. For arm A, which is the intravenous, it was 59.5%, and for arm B, which is the subcutaneous, it was 59.7%. Essentially, there was no difference in pathologic complete response rates. Again, it’s nice to see such a high pathologic complete response rate, close to 60% here.

Then we have to think about safety. [There was almost] no difference in cardiac events, anaphylaxis or hypersensitivity was about the same, 5 cases and 4 cases. Immune-related reactions was slightly higher, 42 patients or 17% in the subcutaneous versus 34 patients or 13.5%. Diarrhea was about the same and cardiac dysfunction, interstitial lung disease, and neutropenia were all similar.

Based on this, the FDA approved [this] breast cancer treatment that can be administered at home by health care professionals.⁷ So they approved Phesgo on June 29, which, again, is a combination of pertuzumab, trastuzumab, and hyaluronidase for injection under the skin to treat patients with HER2-positive breast cancer. The FDA commented that in light of COVID-19 they wanted to focus on these vulnerable patients, so they pushed this through about 4 months ahead of their original FDA goal date.

_REFERENCES:

_{1. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9}

_{2. Piccart M, Procter M, Fumagalli D, et al. Interim overall survival Analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-04.}

_{3. Von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617-628. doi:10.1056/NEJMoa1814017}

_{4. Van Ramshorst MS, van der Voort A, van Werkhoven ED, et al; Dutch Breast Cancer Research Group (BOOG). Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640. doi:10.1016/S1470-2045(18)30570-9}

_{5. Van der Voort A, van Ramshorst MS, van Werkhoven ED, et al; Dutch Breast Cancer Research Group (BOOG). Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): a randomized phase 3 trial. J Clin Oncol. 2020;38(suppl 15):501. doi:10.1200/JCO.2020.38.15_suppl.501}

_{6. Tan AR, Im SA, Mattar A, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: Primary analysis of the phase 3, multicenter, randomized, open-label, two-arm FeDeriCa study. Poster presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract PD4-07.}

_{7. FDA approves breast cancer treatment that can be administered at home by health care professional. News release. FDA. June 29, 2020. Accessed November 30, 2020. https://bit.ly/3qjvUZU}