The Promising Outlook With Immunoconjugate Therapy
By Mark Green, MD & Loreen Brown, MSW
The search for a “perfect” or even “nearly perfect” cancer therapy—one which can identify and kill tumor cells wherever they reside in the host without injuring normal tissues—remains a Sisyphusian task.1 Joining the ranks of combating this task are the development of immunotherapies—treatments that use the body’s own immune system to fight cancer and one that holds great promise for delivering effectiveness with minimal toxicity. Very recently, for example, the anti-CTLA4 antibody, ipilimumab, was approved as a first-line or salvage management for patients with advanced malignant melanoma.
In an advanced disease population, the median overall survival with ipilimumab alone was 10.1 months compared with 6.4 months for a proprietary vaccine alone (hazard ratio [HR] 0.66; P=0.003). However, toxicity was not insignificant. Seven patients experienced on-study deaths related to immune adverse events.2 Moreover, unique response patterns and toxicities associated with ipilimumab therapy led to the development of a new set of immunotherapy-related response and toxicity criteria.3
Alternatively, immunoconjugates represent a matrix of emerging science, including monoclonal antibody targeting of tumor cells and effective linkage of highly toxic therapeutic moieties to the targeting antibody in protected “pro-drug” configurations. This allows systemic trafficking, delivery, internalization, intracellular decoupling of the toxic therapeutic package from the delivery vehicle, and retention of the cytotoxic moiety within the tumor cell target. The conjugated killing agent can be a traditional chemotherapeutic cytotoxic, a natural toxin, or a radiotherapeutic agent. Off-target toxicity is reduced as minimal systemic exposure to the active cytotoxin occurs.
Several immunoconjugates have been approved for treatment in selected hematologic malignancies. Gemtuzumab ozogamicin, in which calicheamicin, a natural enediyne antibiotic, is linked to an anti-CD33 antibody, was accorded accelerated approval in May 2000, with the target disease of acute myeloid leukemia.4 However, the agent was voluntarily withdrawn by its manufacturer in 2011 when Phase 3 data failed to confirm the survival benefit suggested by the Phase 2 data that had led to its initial FDA accelerated approval.4 Another calicheamicin immunoconjugate, inotuzumab ozogamicin, has an anti-CD22 targeting antibody and is currently in Phase 3 testing in selected B-cell neoplasms.5
Last year, brentuximab vedotin, in which an anti-CD30 antibody is linked to the potentially highly toxic antitubulin agent monomethyl auristatin E (MMAE), was approved for patients with relapsed Hodgkin’s disease or anaplastic large cell lymphoma, both of which express CD30. The activity of brentuximab vedotin among patients with advanced, previously treated disease is impressive.6 However, systemic immune suppression has led to an increased risk of progressive multifocal leukoencephalopathy (PML) associated with brentuximab vedotin therapy.7 Other similar agents are currently in development.8
The first immunotoxin conjugate approved for cancer therapy was denileukin diftitox, a recombinant protein with critical components of both human interleukin-2 (IL-2) and truncated diphtheria toxin. The engineered protein binds to the IL-2 receptor and delivers the diphtheria toxin.9 This agent was given accelerated FDA approval in 1999 and received full approval in 2008 for use in patients with progressive CD25-positive cutaneous T-cell lymphoma.10 Usage has been limited, however, and other agents dominate cutaneous T-cell lymphoma therapy.
For patients with relapsed/refractory hairy cell leukemia, a new immunotoxin, moxetumomab pasudotox, has been recently reported to produce an 86% response rate, including 46% complete responses (CRs) in 26 evaluable patients. Only one of the 13 patients who reached CR has had disease recurrence within the first year of therapy.11
In follicular lymphoma, two radioimmunotherapeutics, Yttrium-90 ibritumomab tiuxetan12 and Iodine-131 tositumomab13 are FDA approved as single-agent therapies. Despite high levels of single-agent activity and important improvements in progression-free survival when used following induction chemotherapy, overall utilization is low for a variety of reasons, including reimbursement hurdles.
The Success of T-DM1 Activity
At ASCO this year, a new immunoconjugate entrant, focused on a common solid tumor, had its Phase 3 coming out party, and it was a wow!14 The agent is trastuzumab emtansine (T-DM1), an immunoconjugate that combines the anti-HER2 antibody trastuzumab (T) with the antitubulin chemotherapeutic agent mertansine (DM-1), a derivative of the maytansine. Trastuzumab is a widely utilized anti-HER2 antibody with substantial single-agent activity in patients with HER2-positive breast cancer and HER2-positive gastric carcinoma. The development of trastuzumab ushered in a new paradigm in solid tumor therapy. Yet despite the enrichment driven by HER2 status, objective response rates with trastuzumab as a single agent for patients with metastatic breast cancer (mBC) settle in the 20%–35% range.15
When added to chemotherapy as first-line management for patients with HER2-positive mBC, response rates are high and survival is statistically significantly improved vs chemotherapy alone.16 As a part of adjuvant therapy in patients with completely resected HER2-positive breast cancer, the reduction in risk of disease recurrence contributed by trastuzumab therapy is nearly 50%.17 Even with its single-agent potential for cardiac toxicity, which is heightened further when integrated or sequenced with anthracycline therapy, the clinical impact of trastuzumab in patients with breast cancer is enormous. T-DM1 appears to retain the actions of trastuzumab as a single agent while also delivering the intracellular toxin mertansine specifically to breast cancer cells.
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.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
O’Regan KN, Jagannathan JP, Ramaiya N, et al. Radiologic aspects of immune-related tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy. AJR. 2011;197:W241-W246.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm216458.htm Accessed 5/30/2102.
http://www.pfizer.com/files/news/esmo/inotuzumab_fact_sheet.pdf Accessed 6/01/2012.
Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821.
Adcetris (brentuximab vedotin): Drug Safety Communication—Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity. Posted 1/13/2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm Accessed 5/29/2012.
Webb S. Pharma interest surges in antibody drug conjugates. Nature Biotechnology. 2011;29(4):297-298.
Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001;19:376-388.
http://www.cancer.gov/cancertopics/druginfo/fda-denileukindiftitox Accessed 5/30/2012.
Kreitman RJ, Tallman MS, Robak T, et al. Phase I trial of anti-CD 22 recombinant immunotoxin moxtetumomab Pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 2012;30:1822-1828.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/TherapeuticBiologicApplications/ucm093379.htm Accessed 5/30/2012.
http://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/125011_s024_bexxar.pdf Accessed 5/30/2012.
Blackwell KL, Miles D, Gianni L, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol. 2012;30(suppl; abstr LBA1).
Vogel CL, Cobleigh MA, Tripathy D, t et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719-726.
Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006;24:2786-2792.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283.
Burris HA, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398-340.
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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.