Mamounas Discusses Treatment Combinations in HER2-Positive Early Breast Cancer

Targeted oncology: What regimens are recommended for HER2-positive breast cancer?

Mamonas: at NCCN [National Comprehensive Cancer Network] According to the guidelines, regimens recommended for HER2-positive breast cancer include paclitaxel plus trastuzumab, TCH, [and] TCHP. In the absence of residual disease, continue trastuzumab plus pertuzumab for up to 1 year.Otherwise, if residual disease, adtrastuzumab emtansine [Kadcyla] is optional. Other regimens include an anthracycline and docetaxel or paclitaxel.¹

Which data support pertuzumab versus chemotherapy and trastuzumab in the adjuvant setting?

We have new data from the APHINITY trial [NCT01358877], with pertuzumab, trastuzumab, and chemotherapy as adjuvant therapy. A total of 4,805 patients were randomized equally to chemotherapy, trastuzumab, pertuzumab and chemotherapy, trastuzumab, placebo groups, with approximately 2,400 patients in each group. Randomization occurred within 8 weeks of his surgery, followed by adjuvant anti-HER2 therapy for his 1 year.²

Primary endpoint was invasive disease-free survival [IDFS]However, that definition did not include a second non-breast primary and thus differed slightly from the standardized definition of efficacy endpoint criteria. [tumors]. There was a secondary endpoint of IDFS with a second non-breast primary [tumors] Includes additional endpoints such as DFS, overall survival [OS]recurrence-free interval, distant recurrence-free interval, and health-related quality of life.

Stratification factors were lymph node status, hormone receptor status, and chemotherapy regimen. [anthracycline vs nonanthracycline], geographical regions, protocol versions A and B. There were two versions of the protocol, but it doesn’t matter at this point. The clinical cutoff date for the first analysis was December 2016, when the data were first reported, and the median follow-up was approximately 45.4 months.²

What was the effectiveness of the APHINITY trial?

Data after 8.4 years of follow-up showed an OS rate of 92.7% in the pertuzumab group and 92.0% in the placebo group, which was not statistically significant. [P = .078]. There was a 1.9% advantage in OS in the node-positive cohort, but a ~0.9% disadvantage in the node-negative cohort.

There was no evidence of benefit in the node-negative cohort of this trial, but an even greater effect in the node-positive cohort.but no one sees P. Since this is an exploratory subset analysis, we use values ​​here.³ For the original primary endpoint, IDFS, the difference was approximately 2.6%, with pertuzumab at 88.4% and placebo at 85.8%, with a HR of 0.77. [95% CI, 0.66-0.91]In other words, relapses are reduced by approximately 23%. Some of these additional events occurred in triple-positive, ER-positive, HER-positive patients.

In the node-positive cohort, high-risk patients, the absolute difference was approximately 4.9%, with an unadjusted hazard ratio of 0.72. [95% CI, 0.60-0.87], or a 28% reduction in relapses. For node-negative patients, we were able to superimpose a 1% advantage over the curve with placebo. However, in node-positive patients, the addition of pertuzumab produces a clinically meaningful difference of approximately 5%.³ IDFS in the hormone receptor-positive cohort in the original publication differed by approximately 0.4% across arms. However, the eight-year follow-up shows a difference of about 2.8%, which is not surprising.

ER-negative/HER2-positive population [was] Overrepresented in the initial analysis, we now see an accumulation of events from years 3 to 8. So there is a difference of 2.8% and a relative decrease of 0.75. [95% CI, 0.61-0.92]the reduction in recurrence is 25%, similar to the general population.³

What data support the use of fixed dose combination drug (FDC) subcutaneous trastuzumab/pertuzumab/hyaluronidase-zzxf (Phesgo) in this setting?

Fixed combination therapy with trastuzumab, pertuzumab, and hyaluronidase or subcutaneous injection has been approved by the FDA for HER2-positive breast cancer. It can be used for anything like IV trastuzumab. It can be used as neoadjuvant or adjuvant therapy and as metastatic first-line therapy in combination with docetaxel.^Four There are many studies that back this up.One study supports the combination of pertuzumab and trastuzumab [NCT00545688]another study [NCT03493854] evaluated the pharmacokinetics of FDCs comparing IV trastuzumab and pertuzumab and showed that they exhibited comparable efficacy and at the same drug concentrations.

Other studies led to approval of pertuzumab and trastuzumab [NCT00976989, NCT02132949]. FeDeriCa phase 3 trial [NCT03493854] The research team primarily included patients with stage II to stage IIIc operable or locally advanced inflammatory HER2-positive breast cancer with primary tumors larger than 2 cm or node-positive disease. In other words, neoadjuvant therapy is indicated. It was the researchers’ choice to give both arms what type of chemotherapy or high doses of doxorubicin. [Adriamycin]cyclophosphamide [Cytoxan]paclitaxel [Taxol] [ddAC-T] or 4 cycles of AC followed by docetaxel. One arm received intravenous pertuzumab and trastuzumab, and the other arm received FDC in addition to either paclitaxel or docetaxel. Surgery was performed and the patient remained on his previously assigned regimen.^Five The primary endpoint was non-inferiority of Cycle 7 trough concentrations of pertuzumab. Secondary endpoints were also efficacy with respect to cycle 7 trough concentrations of trastuzumab and pCR comparing the two arms.^Five

How did patients respond to the FeDeriCa trial?

Trough concentration data were not inferior. In fact, numerically, more trastuzumab/pertuzumab was present in the cycle 7 plasma troughs. Of course, FDC doses are slightly different than IV doses. The pCR was identical between the two groups. This, along with the non-inferiority of cycle 7 drug trough concentrations, led to his FDC approval. Adverse events for IV and FDC are similar except for local reactions. Diarrhea, cardiac dysfunction, interstitial lung disease, and neutropenia were all similar in the two groups. Most of them were freshmen and sophomores.^Five

Administration times for IV and subcutaneous FDC are different. Pertuzumab IV is given over 30-60 minutes, followed by observation for 30-60 minutes, followed by trastuzumab for another 30-90 minutes, followed by observation for 120-360 minutes. Therefore, total working time can be up to 6 hours, compared to 5-8 minutes for FDC subcutaneous injection and 15-30 minutes for subsequent observation.⁶

What other trials have investigated this regimen in HER2-positive breast cancer?

The second study on subcutaneous FDC was the PHranceSCa study [NCT03674112], which was a study of patient preferences. They asked patients which formulation they preferred. The researchers included patients with HER2-positive early-stage breast cancer who had completed neoadjuvant pertuzumab, trastuzumab, chemotherapy, and surgery.

160 patients were then randomly assigned 1:1 to either IV trastuzumab plus pertuzumab or subcutaneous FDC pertuzumab plus trastuzumab for 3 cycles. They collected toxicity information and switched patients from infusion to subcutaneous arm or vice versa for 3 more cycles. Patients then chose which formulation to continue for 18 cycles.⁷

Patient preference was the primary endpoint, with a number of secondary endpoints. Briefly, 85% of his patients preferred subcutaneous formulations to IV, and 15% preferred IV. For continuous formulation, 87% chose subcutaneous formulation after experiencing both methods.⁷ The main reasons for preferring subcutaneous administration are the shorter stay in the clinic and the more comfortable administration. When I look at the reasons why I chose an IV, I think it was mostly habit. because they had an IV [they wanted to] I will continue the drip, but most of them wanted a subcutaneous injection.

_References

_{1.NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 3.2022. Accessed February 6, 2023. https://bit.ly/3JExrFT}

_{2. Piccart M, Procter M, Fumagalli D, et al. APHINITY Interim Overall Survival Analyzes (BIG 4-11): A Randomized, Multicenter Two-Way Comparison of Chemotherapy + Trastuzumab + Pertuzumab Versus Chemotherapy + Trastuzumab + Placebo as Adjuvant Therapy in Patients With Operable HER2-Positive Early Breast Cancer A double-blind, placebo-controlled study. Presented at: 2019 San Antonio Breast Cancer Symposium. December 10-14, 2019. San Antonio, Texas. https:// bit. ly/3wZnPOq}

_{3. Loibl S, Jassem J, Sonnenblick A, et al. VP6-2022: Adjuvant pertuzumab and trastuzumab in patients with early-stage HER-2-positive breast cancer in APHINITY: 8.4-year follow-up. Ann Ongol. 2022;33(9):P986-987. Doi: 10.1016/j.annonc.2022.06.009}

_{4. Fesgo. Prescribing Information. Genentech, Inc.; 2020. Accessed on February 6, 2023. https://bit.ly/3HBdQnl}

_{5. Tan AR, Im SA, Mattar A, et al. Federica Study Group. Pertuzumab plus trastuzumab fixed-dose combination therapy (FeDeriCa) for subcutaneous injection and chemotherapy in HER2-positive early-stage breast cancer: a randomized, open-label, multicenter, non-inferiority, phase 3 trial. lancet oncol. 2021;22(1):85-97. Doi: 10.1016/S1470-2045(20)30536-2}

_{6. DuMond B, Patel V, Gross A, Fung A, Weber S. Fixed-dose combination therapy of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive breast cancer: a multidisciplinary approach. J Onkol Pharmacy. 2021;27(5):1214-1221.doi:10.1177/1078155221999712}

_{7. O’Shaughnessy J, Sousa S, Cruz J et al. PHrance SCa study group. Fixed Dose Combination of Pertuzumab and Trastuzumab is Preferred for Subcutaneous Injection in Patients with HER2-Positive Early Breast Cancer (PHranceSCa): A Randomized, Open-label, Phase II Trial. Euro J Cancer. 2021; 152:223-232. Doi: 10.1016/j.ejca.2021.03.047}