Unprecedented efficacy of latest HER2-targeting agents can extend life but at significant cost

Breast cancer is the second most common cancer in the world, and the most common cancer in women. In 2013, approximately 261,000 women were diagnosed with this disease in the United States alone.¹ When diagnosed in the earliest stages, such as ductal carcinoma in situ and stage 1, the 5-year survival rate is almost 100%. If diagnosed later, or if the disease progresses to advanced breast cancer, survival rapidly decreases. Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents about 20% of cases, and before the introduction of HER2-targeting therapies, had the worst prognosis of all breast cancer subtypes.

Since 1998, when FDA approved the HER2-targeting monoclonal antibody Herceptin (trastuzumab, Roche/Genentech), the treatment of HER2-positive disease has been revolutionized, bringing the prognosis close to that of HER2-negative disease. Alongside Herceptin, GlobalData expects the new generation of HER2-targeting agents, including Perjeta (pertuzumab, Roche/Genentech) and Kadcyla (T-DM1/trastuzumab emtansine, Roche/Genentech), to further revolutionize this setting. These advances, however, come with a significant cost to the healthcare system, a factor that GlobalData anticipates will become a greater concern in the United States, particularly as cost effectiveness becomes more pertinent for formulary stakeholders. 

In 2012, FDA approved the use of the HER2:HER3 dimerization inhibitor Perjeta, in combination with Herceptin and docetaxel, for the treatment of HER2-positive breast cancer in the first-line metastatic setting. Based on GlobalData’s primary research, this combination has rapidly become the new standard of care in this setting in the United States. Regulatory approval was based on a statistically significant progression-free survival benefit in the placebo-controlled, phase 3 CLEOPATRA trial.² Data for overall survival (OS), the gold-standard efficacy endpoint, had been eagerly awaited and were announced at the European Society for Medical Oncology 2014 Congress last September. Perjeta, in combination with Herceptin and docetaxel, demonstrated an unprecedented 15.7-month survival benefit over the Herceptin, docetaxel, and placebo control arm, resulting in a median OS of 56.5 months (4.6 years). The Perjeta combination regimen was well tolerated, with no significant safety signals reported.

GlobalData anticipates these positive outcomes data to further cement Perjeta’s place in the first-line metastatic setting. This impressive clinical benefit comes at a high premium, however, in terms of annual cost of therapy (ACOT). One year of therapy with Perjeta in combination with Herceptin can cost over $110,000 in the United States, compared with Herceptin alone, the previous standard of care, at approximately $40,000. In the first half of 2014, Perjeta sales reached $416 million, showing that this drug is becoming an important first-line therapy regardless of its cost.

The second-line metastatic setting is also undergoing significant changes. GlobalData’s primary research finds the current gold-standard second-line therapy for HER2-positive metastatic breast cancer is the recently approved Kadcyla. Kadcyla, an antibody-drug conjugate (ADC), which consists of the HER2-targeting monoclonal antibody Herceptin covalently linked to the cytotoxic agent DM1, was approved by FDA in 2013, becoming the first ADC to be used in breast cancer. Key opinion leaders interviewed by GlobalData are impressed with Kadcyla’s robust efficacy and toxicity profiles. Similar to Perjeta, Kadcyla is a premium-priced breast cancer therapy, with an ACOT of up to $150,000 in the US. Despite this high price, Kadcyla has also enjoyed rapid uptake on the US market, garnering sales of $244 million in the first half of 2014.

Now that Perjeta and Kadcyla have become key elements of the HER2-positive breast cancer armamentarium, GlobalData expects the manufacturer to focus on positioning the combination of these targeted treatments in the first-line metastatic and pre-metastatic settings. Investigations into the combination of the agents in these settings are already under way. The phase 3 MARIANNE trial is investigating Kadcyla in combination with Perjeta versus either Kadcyla alone or Herceptin in combination with a taxane in the first-line metastatic setting.³ Key opinion leaders interviewed by GlobalData expect positive trial results for this combination of Kadcyla and Perjeta, establishing it as the preferred first-line therapy in this setting. Questions will remain, however, especially on the best sequential use of the HER2-targeting agents Herceptin, Perjeta, Kadcyla, and their combinations, regarding both clinical outcomes and cost control. With Kadcyla costing over $12,000 per month, and Perjeta alone at over $6,000 per month, the combination of these agents is expected to carry an extremely high price tag, especially as they are likely to be prescribed until disease progression. A more affordable first-line option may remain the combination of Perjeta with Herceptin, and later, biosimilar trastuzumab (following Herceptin’s patent expiry in 2019), saving Kadcyla monotherapy for the second-line setting, when patients ultimately relapse. GlobalData anticipates that healthcare providers may consider this sequence to be a more cost-effective strategy. This is especially true within the 5EU (France, Germany, Italy, Spain, United Kingdom), a region which is undergoing increasing restrictions on healthcare expenditures.

Patients with early-stage HER2-positive breast cancer are also set to benefit from the new generation of HER2-targeting agents. One of the key trends in this market, exemplified by the development of Herceptin, is to introduce drugs established in the metastatic setting into the earlier, pre-metastatic setting, which constitutes the largest patient population with this disease. Perjeta was approved as a neoadjuvant therapy in the US in 2013, joining Herceptin as a treatment option for resectable HER2-positive patients. GlobalData expects Kadcyla to enter the adjuvant setting in combination with Perjeta in 2019. From the payer’s perspective, the ACOT for this combination could be as high as in the metastatic setting. Duration of therapy in the adjuvant setting is expected to remain consistent at 1 year of treatment, however, resulting in a more predictable outlay. With over 45,000 patients eligible for this new regimen, healthcare authorities will need to plan the most cost-effective course of action in managing these patients.

Overall, there is no doubt that these drugs are drastically changing the outlook for patients with HER2-positive breast cancer, and oncologists will be eager to maximize these treatment options. From a financial perspective, GlobalData expects the rapid uptake of these drugs across the first-line and adjuvant settings to drive the growth of the US HER2-positive market at a strong compound annual growth rate of 12.7% to $7.9 billion by 2023, with Perjeta and Kadcyla together representing 84% of the US market. This uptake, however, is expected to put further financial strain on the healthcare system. From a health economics perspective, research still needs to be done to determine the most clinically and cost-effective treatment algorithms. Ultimately, GlobalData believes that the exciting prospect of curative treatments in the adjuvant setting with these latest monoclonal antibody therapies, along with the implication of longer-term healthcare savings, albeit with an increased immediate cost, could be the most important dynamic for payers to consider in this market over the next few years.

References

1.     GlobalData. PharmaPoint: HER2-positive breast cancer – global drug forecast and market analysis to 2023. London, UK: September 2014, GDHC86PIDR.

2.     ClinicalTrials.gov. US National Institutes of Health. A study to evaluate pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in previously untreated HER2-positive metastatic breast cancer (CLEOPATRA), NCT00567190.  http://clinicaltrials.gov/show/NCT00567190. Accessed October 17, 2014.

3.     ClinicalTrials.gov. US National Institutes of Health. A study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab (Herceptin) plus a taxane in patients with metastatic breast cancer (MARIANNE), NCT01120184.  http://clinicaltrials.gov/show/NCT01120184. Accessed October 17, 2014.

Dr Mallinson is GlobalData’s analyst covering oncology and hematology.

Disclosure information: The author reports no financial disclosures as related to products discussed in this article.

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