Subcutaneous Pertuzumab/Trastuzumab Combo Continues to Prove Safe, Effective in HER2+ Breast Cancer

Subcutaneous (SC) delivery of fixed-dose adjuvant pertuzumab (Perjeta) plus trastuzumab (Herceptin) proved to have favorable tolerability, with a safety profile consistent with that seen with intravenous (IV) delivery of the regimen in patients with HER2-positive breast cancer, according to data from a long-term analysis of the phase 2 PHranceSCa study (NCT03674112).1

Findings presented at the 2023 ESMO Breast Cancer Annual Congress showed comparable rates of adverse effects (AEs) in patients who received the regimen subcutaneously (n = 138) or intravenously (n = 21) in the continuation period, with the exception of grade 1 or 2 local injection site reactions (9.4% vs 0%). Notably, no patients experienced grade 3 or higher anaphylaxis, and no new safety signals were observed.

Moreover, the 3-year invasive disease-free survival (iDFS) rate was 94.17% (95% CI, 90.47% - 97.87%) in the SC FDC arm; there were 11 iDFS events and 2 deaths. The 3-year overall survival (OS) rate was 98.71% (95% CI, 96.92%-100%).

“Efficacy data are immature but show high event-free rates for iDFS and OS at 3 years, consistent with the known clinical benefit of pertuzumab and trastuzumab,” lead study author Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, and her colleagues, wrote in a poster on the data.

The randomized, open-label, international, multicenter, crossover study enrolled patients aged 18 years or older with histologically confirmed inflammatory, locally advanced or early HER2-positive breast cancer.2Patients were required to have received neoadjuvant pertuzumab, trastuzumab, and chemotherapy before undergoing surgery for their disease. Other key eligibility criteria included an ECOG performance status of 0 or 1 and left ventricular ejection fraction of 55% or greater by echocardiography or multiple-gated acquisition scan.

Patients were ineligible for the study if they had received previous systemic therapy, such as chemotherapy, immunotherapy, HER2-targeted agents, endocrine therapy, and antitumor vaccines for their disease. Exclusion criteria also included serious cardiac illness or medical conditions and impaired or inadequate function of organs or bone marrow.²

Study participants were randomly assigned 1:1 to receive either 3 cycles of SC pertuzumab and trastuzumab followed by 3 cycles of IV pertuzumab and trastuzumab or the reverse. Dose levels for the SC regimen were 600 mg of pertuzumab and 600 mg in 10 mL of trastuzumab; the IV regimen was delivered at dose levels of 429 mg and 6 mg/kg, respectively.

Loading doses were administered at the beginning of the treatment course for patients who received their last neoadjuvant dose of IV pertuzumab and trastuzumab 6 weeks or longer before study entry, or those who did not receive their last study treatment in less than 6 weeks.

For the SC pertuzumab and trastuzumab, loading dose levels were 1200 mg and 600 mg in 15 mL, respectively; for the IV regimen, the dose levels were 840 mg and 8 mg/kg, respectively. After the crossover period, patients continued treatment for up to 18 cycles with either SC injection or IV infusion according to personal preference.

The primary objective of the PHranceSCa study was to assess patient preference for route of administration of pertuzumab and trastuzumab in the modified intention-to-treat (mITT) arm. Patient preference was defined as the proportion of patients who preferred SC delivery based on question 1 of a Patient Preference Questionnaire (PPQ). Other assessments included a Therapy Administration Satisfaction Questionnaire, Healthcare Professional Questionnaire (HCPQ), as well as health-related quality of life (QOL) and safety assessments.

In the original ITT population (n = 160), the median age of patients in both arms was 47 years (range 22-80). All patients in this population were women. Most patients identified as White (80.6%), followed by Asian (7.5%), Alaskan Natives or American Indians (5.0%), Black (2.5%), and unknown (4.4%). Patients had a median baseline weight of 68 kg (range 46.4-119.0). In terms of ECOG performance status, 87.5% of patients had a status of 0 and 12.5% had a status of 1. At the time of disease presentation, 85% of patients had stage II to IIIA breast cancer and 15% had stage IIIB to IIIC disease.

More than half of patients (58.8%) displayed invasive carcinoma of no special type. Other histological subtypes included invasive lobular carcinoma (7.5%), invasive micropapillary carcinoma (1.3%), mucinous carcinoma (0.6%), apocrine carcinoma (0.6%), and other (34.4%). The percentage of patients with grade 1 disease was 1.9%; 45% had grade 2 histology, 41.9% had grade 3 histology, 1.9% had no residual tumor. Histological grade was unknown in 9.4% of patients. 

The percentage of patients who had received 4 or more cycles of neoadjuvant pertuzumab, trastuzumab and chemotherapy was 90.6%. Prior chemotherapy regimens included anthracycline plus taxanes (67.5%), carboplatin plus taxanes (28.1%), or taxanes only (4.4%). Pathologic complete responses to neoadjuvant therapy were achieved in 63.8% of patients and residual disease was observed in 36.3%. Sixty-five percent of patients had estrogen receptor (ER)–positive and/or progesterone receptor (PgR)–positive breast cancer and 35% of patients had ER-negative/PgR-negative disease.

Data initially published in the European Journal of Cancer in 2021 showed that 85% (95% CI, 78.5%-90.2%) of all patients (n = 160) preferred SC administration, 13.8% preferred IV delivery, and 1.3% had no preference. Common reasons given for the SC option included reduced time in the clinic (n = 119) and comfort during administration (n = 73). Moreover, 88.1% of patients reported being very satisfied/satisfied with SC injection vs 67.5% who received IV infusion, and 86.9% chose to continue SC delivery. The toxicity profile for each delivery method was consistent with known clinical data for pertuzumab and trastuzumab.

At the 2023 ESMO Breast Cancer Annual Congress, investigators shared updated efficacy and safety data after 3 years of follow-up.¹

A total of 159 patients from the ITT population in the PHranceSCa trial continued treatment, and 148 completed the follow-up period. Twenty-one patients selected IV delivery, and 138 patients chose SC delivery. The median number of treatment cycles received during the continuation period was 8 in both arms (range for IV, 5-9; range for SC, 3-10). 

Additional safety analysis of patients during the continuation period showed that in both the SC delivery arm and IV delivery arm, 66.7% of patients experienced an AE of any grade. In the SC delivery arm, grade 3 to 5 AEs were seen in 5.1% of patients and serious AEs were observed in 2.9%. Cardiac AEs were reported in 0.7% of patients and anaphylaxis or hypersensitivity was experienced by 1.4% of patients. These events were all grade 1/2. Administration-related reaction occurred in 11.6% of patients and consisted of local injection-site reaction (9.4%) and systemic injection reactions (1.4%).

Comparatively, 9.5% of patients in the IV delivery arm experienced grade 3 to 5 AEs, and cardiac AEs were seen in 4.8% of patients. No serious AEs or anaphylaxis/hypersensitivity events were observed in this group. Administration-related reactions occurred in 4.8% of patients and consisted entirely of low-grade systemic infusion reactions. 

The most common AEs reported in 5% or more of patients included diarrhea (SC arm, 10.9%; IV arm, 19%), injection site reaction (9.4%; 0%), arthralgia (4.3%; 14.3%), fatigue (5.1%; 4.8%), pruritus (5.1%; 0%), pain in extremity (2.9%; 9.5%), rash (1.4%; 14.3%), hot flush (2.2%; 0%), headache (0.7%; 9.5%), myalgia (0.7%; 9.5%), bone pain (0%; 9.5%), and radiation skin injury (0.7%; 0%).

Dose interruption due to AEs occurred in 5.8% and 4.8% of patients, respectively. No patients discontinued treatment due to AEs in the SC group vs 4.8% of those in the IV group.

Investigators also assessed QOL using the EORTC QLQ-C30 questionnaire. Mean changes in QOL from baseline up to 3 years between the arms were minimal, according to the study investigators. Improvements in role and social functioning, as well as reduction in financial difficulties, were the only clinically meaningful changes from baseline that were observed.

Disclosures: Dr O'Shaughnessy reports having financial and personal interests with, and serving on an advisory board for AbbVie, Agendia, Amgen, Aptitude, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunome, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, and Sanofi.

References

1. O’Shaughnessy J, Sousa S, Jurado JC, et al. Efficacy and safety of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer: Long-term data from the PHranceSCa study. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 97P.
2. O’Shaughnessy J, Sousa S, Cruz J, et al. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study. Eur J Cancer. 2021;152:223-232. doi:10.1016/j.ejca.2021.03.047