Pertuzumab is a recombinant humanised monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER-2) preventing its binding with other members of the HER family. This inhibits intracellular signalling, arresting cell growth and inducing apoptosis. Additionally, pertuzumab mediates an immune response that lyses tumour cells. Pertuzumab differs to trastuzumab, as it binds to a different extracellular region of the HER-2 antigen.

Pertuzumab has proven to show additional benefit to metastatic HER-2 positive breast cancer patients who progressed on trastuzumab. These favourable results prompted pertuzumab to be researched in the HER-2 positive neoadjuvant setting; NeoSphere clinical trial. The NeoSphere trial demonstrated that early or locally advanced HER-2 positive breast cancer patients who received pertuzumab in addition to trastuzumab plus chemotherapy (docetaxel), in the neoadjuvant setting achieved a higher proportion of pathological complete response (pCR). Given this trial data, it is important to note that pCR still requires verification as to if it can be used as a reliable primary endpoint and early indicator of benefit in neoadjuvant studies for HER-2 targeted agents.

The NeoSphere trial consisted of four treatment groups; A (trastuzumab plus docetaxel), B (pertuzumab, trastuzumab plus docetaxel), C (pertuzumab and trastuzumab) and D (pertuzumab plus docetaxel). Group B had a significantly improved pCR rate of 45.8% compared with group A (29%), D (24%) and C (16.8%). At five year follow up, Group B had the highest progression and disease-free survival, and patients who achieved total pCR in the study had longer progression-free survival than those who did not. In terms of safety and tolerability, the number of serious adverse events was similar across groups A, B and D and lowest in C.

The TRYPHAENA trial aimed to evaluate the cardiac safety of the combination of pertuzumab, trastuzumab and chemotherapy in the neoadjuvant setting for patients with early HER-2 positive breast cancer. The study concluded that the combination of pertuzumab, trastuzumab and chemotherapy resulted in low rates of left ventricular systolic dysfunction.

Published clinical trial data on the efficacy and safety of pertuzumab in the neoadjuvant setting for HER-2 positive locally advanced or early breast cancer patients has lead to worldwide prescribing of pertuzumab to extend to this scope of practice. In Australia, currently the PBAC has not approved PBS funding for pertuzumab for neoadjuvant treatment in patients with HER-2 positive locally advanced or early breast cancer. However, ROCHE has established the HerStart co-pay program, which assists patients with funding neoadjuvant pertuzumab therapy.

References:

  1. Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010; 28: 1138–44.
  2. Gianni L, Pienkowski T, Im YH, Roman  L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory or early-stage HER-2 positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2011; 13(1): 25-32.
  3. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. Five year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory or early-stage HER-2 positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016; 17: 791-800.
  4. Hoffmann-La Roche Limited. Perjeta® product monograph. Mississauga, Ontario; 12 April 2013.
  5. Keating GM. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer. Drugs 2012; 72(3): 353-60.
  6. Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012; 366: 2438–41.
  7. Rossi S (editor). Australian Medicines Handbook. Adelaide: AMH; 2021.
  8. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER-2 positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013; 24(9): 2278-84.

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