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Treatment of HER2+ Breast Cancer: Kanjinti, a biosimilar to trastuzumab

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It is estimated that 15% to 20% of women with newly diagnosed breast cancer have tumours that over-express human epidermal growth factor receptor 2 (HER2). These tumours tend to be more aggressive and are associated with poorer outcomes compared to other subtypes. Assuringly, the advent of targeted anti-HER2 therapies in the 1990s have lead to markedly improved outcomes for these patients.

Trastuzumab (Herceptin®) by Roche, was the first anti-HER2 antibody developed and has been studied in adjuvant and neoadjuvant settings for the treatment of HER2 over-expressing breast cancer, demonstrating improvements to key disease endpoints. Its place-in-therapy is cemented in European and American oncology guidelines as the standard first-line treatment for HER2+ early and advanced breast cancer. The clinical benefit of trastuzumab has also been demonstrated in other malignancies characterised by HER2 over-expression, in particular, gastric cancer.

In May 2021, HSA approved the use of Amgen’s trastuzumab biosimilar, Kanjinti, for all registered indications of the trastuzumab reference product (RP), Herceptin, based on a totality of evidence (TOE) encompassing comprehensive comparative pharmacokinetic (PK) studies and a single Phase III study, LILAC, conducted in HER2+ early breast cancer (EBC) women. Kanjinti binds to the extracellular domains of HER2 and inhibits the proliferation of HER2 overexpressing tumour cells. The drug is available in Singapore as a 150mg or 440mg powder for reconstitution, administered via an intravenous infusion. 

Kanjinti’s Phase III global equivalence study, LILAC, randomized 725 EBC patients to receive Kanjinti or trastuzumab RP, Herceptin. The primary endpoint was pathologic complete response (pCR), which was achieved in 172 (48%) of 358 patients who received Kanjinti and 137 (41%) of 338 who received the trastuzumab RP. This yielded a risk difference of 7.3% (90% CI 1.2013.4) and relative risk (RR) of 1.188 (1.033-1.366). 

Unique to LILAC was a switch design in three arms: Kanjinti in the neoadjuvant and adjuvant setting, RP in the neoadjuvant and adjuvant setting, or neoadjuvant RP followed by adjuvant Kanjinti. The frequency, type and severity of adverse events (AEs) were comparable across treatment arms, providing encouraging safety and immunogenicity data for the practical consideration of switching Herceptin patients to Kanjinti. In addition, cardiotoxicity remains of particular concern with trastuzumab therapy. 7 patients had cardiac failure during the neoadjuvant phase (6 patients in the Kanjinti group and 1 in the trastuzumab RP group), although none of the cardiac events were coincident with reduced left ventricular ejection fraction. Clinical cardiac events, all grade 1–2, developed in 2% of Kanjinti patients and <1% of trastuzumab RP patients. Patients were able to complete all planned doses of the drug with no exacerbation of symptoms.

Clinical Considerations: Biosimilars of Trastuzumab 

In 2018, trastuzumab accounted for the highest drug expenditure in Singapore’s public sector at SGD$23 million. Following Herceptin’s patent exclusivity terminus in late 2019, biosimilar candidates have greatly reduced the financial burden of biologic treatments. To date, 4 trastuzumab biosimilars are approved for use in Singapore by the HSA, improving treatment access to the first-line therapy. The approved biosimilars have demonstrated equivalence or non-inferiority to the RP with similar safety signals. Notably however, the various agents have followed diverse pathways in their clinical development, with distinct clinical trial design, patient population and endpoints. In addition, the expedited drug development process uses short-term surrogate endpoints such as pCR and overall response rate (ORR), instead of traditional “gold standard” survival endpoints for evaluating cancer therapies. To date, Ogivri has the longest follow-up data, with no differences in survival outcomes at 3 years compared to Herceptin in patients with HER2+ metastatic breast cancer (MBC). Table 1 provides a brief comparison of the relevant Phase III biosimilar studies.

When evaluating the use of this novel category of therapeutics, clinicians must ultimately consider the differences in biosimilarity exercise approach. Awareness and education regarding the use of biosimilars is a key factor in ensuring access to safe and potentially cost-effective treatments for patients. 

Table 1. HSA-approved trastuzumab biosimilars

Biosimilar Generic Name (Brand Name, Pharmaceutical Company) Phase III Randomised Clinical Trial (RCT) Design Primary Efficacy Endpoint(s) 

Biosimilar vs Reference Product

Trastuzumab-anns (Kanjinti, Amgen) LILAC

  • N=725; EBC
  • Randomized 1:1
  • Neoadjuvant therapy followed by adjuvant treatment up to 1 year
pCR in breast tissue and axillary lymph nodes at 12 months: 48.0% vs 41% 

  • Risk difference: 7.3% (90% CI 1.2013.4) 
  • Relative risk (RR): 1.188 (1.033-1.366)
Trastuzumab-dkst (Ogivri, Mylan and Biocon) HERITAGE

  • N=500; MBC
  • Randomized 1:1
  • Biosimilar or RP with taxane for 24w then either alone until disease progression or loss of tolerability
Overall response rate (ORR) at 24 weeks: 69.6% vs 64.0%   

  • ORR ratio 1.09 (90% CI: 0.974-1.211)
  • ORR difference 5.54 (95% CI -3.08-14.04)  

      

Median overall survival (OS) at 36 months: 35.0 months vs 30.2 months  

  • OS HR 0.9 (95% CI 0.70-1.17)
Trastuzumab-qypp (Trazimera, Pfizer) REFLECTIONS 02

  • N=707; MBC
  • Randomized 1:1
  • First-line treatment with at least 6 cycles of biosimilar or RP, with paclitaxel
ORR (week 33): 62.5% vs 66.5%

  • Risk ratio for ORR 0.940 (95% CI: 0.842-1.049)

OS at 1 year: 89.31% vs 87.36%

  • Median not reached, no statistically significant difference
Trastuzumab-pkrb (Herzuma, Celltrion and Teva)
  • N=549; EBC
  • Randomized 1:1
  • Equivalence trial
  • Neoadjuvant therapy with 8 cycles of biosimilar or RP with docetaxel followed by an adjuvant period of up to 1 year
pCR: 48.8% vs 44.1%

Ongoing 3-year post-treatment follow-up

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