July 2012 Edition Vol.11, Issue 7

The Promising Outlook With Immunoconjugate Therapy

The Promising Outlook With Immunoconjugate Therapy

The activity of T-DM1 on a day-1-every-3-weeks schedule in patients with mBC was defined in a 112-patient, single-arm Phase 2 trial reported by Burris et al in 2009 and published in 2011.18 The primary efficacy endpoint was overall response rate as defined by independent radiology review. The selected schedule was 1 dose every 3 weeks. Treated patients had HER2-positive disease and had received both trastuzumab and chemotherapy previously. Seventy-five of the 112 patients (67%) had progressed while on trastuzumab alone, and 60% had also been treated with lapatinib before study entry. Overall response rate by independent radiology review was 25.9%: 28% among those patients with prior progression on trastuzumab alone, and 24% among those who previously had received both trastuzumab and lapatinib.

Based on these data, the study sponsor filed a biologic license application (BLA) for accelerated approval. The FDA refused to accept the BLA based, at least in part, on its assessment that “the TDM-1 trial did not meet the standard for accelerated approval because all available treatment choices approved for the metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.”19 In other words, the FDA was looking for an active-control arm benchmark against which to better assess the efficacy of the investigational agent in the patients elected for study participation.

As of the June 3, 2012, ASCO plenary session, the results of the pivotal, Phase 3, randomized, open-label “EMILIA” trial of T-DM1 in patients with HER2-positive locally advanced or mBC are in the public domain.14 A total of 991 patients participated in the trial. All had prior taxane and trastuzumab and had progressed on metastatic therapy or within 6 months of adjuvant therapy. Patients were assigned to either T-DM1 or an active, FDA-approved comparator arm of capecitabine and lapatinib. The median time between completion of prior trastuzumab therapy and study entry was 1.5 months. Co-primary study endpoints were progression-free survival based on central radiographic assessment and overall survival.

There was clearly increased activity with the T-DM1 immunoconjugate compared with capecitabine-lapatinib, while serious toxicity was reduced in the T-DM1-treated patients. Median progression-free survivals were 9.6 months among T-DM1-treated patients compared with 6.4 months with capecitabine-lapatinib (HR 0.650; 95% confidence interval [CI]: 0.55, 0.77; P<0.0001). Grade 3 or greater adverse events and discontinuations of therapy due to adverse events were all reduced among T-DM1-treated patients compared with those assigned to the capecitabine-lapatinib doublet.

A preplanned interim analysis of survival was also presented. Median overall survival has not yet been reached among T-DM1 patients and is 23.3 months among those randomized to capecitabine-lapatinib (HR 0.621; CI: 0.48, 081; P=0.0005). As of this interim analysis, the boundary for early declaration of overall survival superiority for T-DM1 (HR 0.617; P=0.0003) has not been crossed. Additional follow-up of the overall survival endpoint is ongoing.

Final Thoughts and Considerations

Although it initially had a slow start, immunoconjugate therapy is here to stay. Look for it to have a substantially expanded role in cancer patient care over the next several years. The FDA has accepted the updated BLA submission for T-DM1 that includes the EMILIA data, and ODAC gets to provide input on June 30. The betting odds are on very accelerated review and approval, with many other promising agents to follow in the short-term. Looking into the future with about 227,000 women in the United Stated estimated to be diagnosed with breast cancer in 2012, T-DM1 has a potential to become an important therapeutic option for about one-fifth of patients with breast cancer whose tumors are overexpressing HER2 protein.

However, given the complex nature of many of these therapies and the potentially narrow FDA-approved indications, the cost of immunoconjugate therapies historically has been, and will likely continue to be, quite high. Therefore, while each product will have unique needs, manufacturers should focus on the following considerations when launching immunoconjugate products:

These complex therapies have unique distribution needs. Creating the “right” distribution strategy for your product goes hand in hand with maximizing patient access.

Understanding the current and predicting the future payer mix of new products coming to market is more challenging given the ever-changing landscape and as healthcare reform implementation continues to unfold. However, an accurate understanding of the mix of payers for each unique product focuses limited resources in the areas to have the largest impact. Translation of the evidence into real-world messaging that creates value for and resonates with all stakeholders—providers, payers, patients, and employers—will expand the product’s initial uptake and long-term use. Such data add depth to the product’s unique and superior value proposition.

Design a distinctive support program that matches the needs of your patients and providers. Benchmarking and exposure analyses provide insights to help understand the competitive marketplace while simultaneously taking into account the unique needs of specific patient populations.

Lastly, do not overlook the importance of integrating safety and risk management strategies in lock-step with other commercial goals to maximize stakeholder benefit and minimize risk.

As payers continue to struggle with the dichotomy of controlling costs while increasing quality and decreasing variability, immunoconjugates will likely complicate the marketplace. Payers, even in the oncology space, are more often requesting data to understand the value that new cancer therapies provide. So in addition to uncovering clinically relevant compounds, manufacturers will also need to focus efforts on preparing the market for commercialization in order to ensure a successful launch.  


Le Mythe de Sysiphe. Albert Camus Gallimard. 1942.

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About the Contributor

Mark Green is a medical oncologist and Chief Medical Officer at Xcenda. Loreen Brown is a Senior Vice President, who leads the Access and Reimbursement consulting teams at Xcenda. Xcenda (www.Xcenda.com) is a premier, full-service consultancy and leading managed markets agency. For more than 2 decades, global companies as well as emerging pre-commercialization phase firms have turned to Xcenda for strategic insights, HEOR expertise, and reimbursement support.


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