New entrants into the oncology marketplace can distinguish themselves in a number of ways. One approach is to be first-in-class with a novel mechanism of action (MOA) – this is true for over one-half of the pipeline agents in pivotal development. Another development strategy is to target an indication with high unmet need, offering a valuable new treatment approach for patients with few options. Of course, all cancer indications have rather high unmet need compared with non-oncology indications due to the life-threatening nature of the disease; however, among the numerous cancer indications, the level of need may vary considerably. Among 69 pipeline agents that are in pivotal clinical development in oncology, only one-third of ongoing pivotal studies with pipeline agents are being conducted in indications with relatively high unmet need1 (Figure 1). These indications include relapsed refractory acute leukemias; second-line therapy for gastric cancer, pancreatic cancer and hepatocellular carcinoma; and fourth-line therapy for multiple myeloma and renal cell carcinoma.
Areas of unmet need may be growing as clinical research continues to identify new biomarkers that identify mechanisms that drive a particular patient’s tumor or that confer a worse prognosis. Patients in these categories may have treatment options in the available armamentarium, but those options may be less effective than a targeted agent directed at their tumor’s specific molecular profile, making this a new area of unmet need. However, despite the oncology community’s growing focus on personalized medicine, only 22% of pipeline agents currently in pivotal trials are being developed in a biomarker-defined patient population. Novel biomarker populations that are currently being studied in pivotal trials in oncology are summarized in Table 1. Many more are being evaluated in early-stage exploratory studies and could begin to affect the market in the next five years.
Through extensive analysis based on a combination of product and indication attributes,2 Kantar Health has evaluated and rated these 69 pipeline agents to identify those with the greatest likelihood of clinical impact in the next three years. Five pipeline agents have emerged as having significant “breakthrough” potential, based primarily on the merits of their clinical data and independent of target indication attributes. We believe these five agents have the potential to dramatically improve efficacy outcomes and may transform the standard of care in their target indications.
1. Dabrafenib + Trametinib
GlaxoSmithKline is developing the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in melanoma patients with the BRAF-mutation. As monotherapies, neither dabrafenib nor trametinib raises eyebrows. In combination, however, they may be a force to be reckoned with. In a randomized Phase II trial, the combination significantly prolonged progression-free survival (PFS) compared with dabrafenib alone while also reducing the incidence of key toxicities associated with this class of agents. These data are currently being explored in Phase III trials, but Kantar Health anticipates the National Comprehensive Cancer Network (NCCN) will recommend use of the combination regimen based on the highly positive randomized Phase II data, giving this combination a near-term impact on the melanoma market (approval of each agent as a monotherapy is expected in 2013).
The Bruton’s tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor pathway, making ibrutinib a novel mechanistic approach to the treatment of B-cell malignancies. Ibrutinib has demonstrated robust activity in heavily pretreated chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Furthermore, ibrutinib is amazingly well-tolerated, with very few serious adverse events. The lack of significant toxicity opens the door for it to be combined with current standards of care. Capitalizing on the early efficacy signals, Pharmacyclics and Johnson & Johnson are pursuing multiple pivotal trials of ibrutinib in relapsed/refractory CLL and MCL.
The PI3K pathway undoubtedly represents one of the hottest drug targets in oncology. Idelalisib is the most advanced of the isoform-specific PI3K inhibitors, and it made a big splash when it produced high response rates and PFS in heavily pretreated CLL and non-Hodgkin’s lymphoma (NHL) patients in early trials. Although it’s not without toxicity, the observed toxicities don’t overlap with those associated with current standards of care in CLL and NHL, leaving open the possibility for idelalisib to be combined with existing regimens. Following its 2011 acquisition of Calistoga, Gilead has charged ahead with the development of idelalisib, initiating four Phase III trials in relapsed/refractory CLL and indolent NHL.
Nivolumab (anti-PD-1 monoclonal antibody, BMS) demonstrated impressive activity in a large, first-in-man Phase I trial, with durable objective responses observed in several solid tumors. On top of these efficacy outcomes, nivolumab impressed with its rather tolerable safety profile. From this single (albeit large) trial, Bristol-Myers Squibb plowed ahead, initiating five Phase III trials in three tumor types (melanoma, NSCLC and renal cell carcinoma). The strong Phase I data, good safety profile, broad applicability across multiple tumors and the possibility for a predictive biomarker all contribute to nivolumab’s potential breakthrough status.
5. Palbociclib (PD-0332991)
PD-0332991 (palbociclib; Pfizer) wowed the audience at the 2012 San Antonio Breast Cancer Symposium (SABCS) annual meeting with an 18+-month improvement in median PFS in a randomized Phase II trial of letrozole with or without PD-0332991 as first-line therapy for ER+ metastatic breast cancer. As a CDK 4/6 inhibitor, it will be first-in-class if it hits the market, although inhibitors of other CDKs are also in late-stage development. Although currently in pivotal development only for metastatic breast cancer, the eventual development of this agent in earlier-stage breast cancer can be foreseen, and Pfizer is also investigating the drug in a number of other solid tumors. With broad applicability and stunning Phase II data, PD-0332991 has the ability to be a breakthrough agent in the treatment of cancer.
These five agents are just the tip of the iceberg. The oncology pipeline continues to grow, and the number of novel MOAs in development offer significant promise toward improving outcomes in a variety of indications. The past couple of years have seen some significant breakthroughs in cancer management, and the next few years have great potential to similarly transform care and outcomes.
1. The level of unmet needs was calculated based on the number of existing treatment options in the target indication (with fewer treatment options correlating with higher need), the rate of treatment (with high non-treatment rates correlating with higher need), and efficacy outcomes achieved with current options (with short survival times correlating with higher need). High overall scores for the sum of these three attributes were considered to be a high unmet need, whereas low overall scores were considered to be a low unmet need.
2. Attributes that were scored included mechanistic innovation, strength of prior published data, target indication population size, and level of competition. For more in-depth information on Kantar Health’s scoring methodology, please e-mail firstname.lastname@example.org.
By: Stephanie Hawthorne, PhD, Director, Kantar Health
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