Mining the Pipeline: Leading Investigational Products and Areas of Unmet Need

Oncology Business News®, June 2013, Volume 2, Issue 2

The oncology pipeline is crowded, despite the fact that the agents in development target a broad range of tumor types.

Figure 1. Number of Trials Each Agent

is Participating In

Source: Kantar Health

Oncology continues to be a significant focus of development in the pharmaceutical market. The field is crowded, despite the fact that the agents in development target a broad range of tumor types. Kantar Health has profiled 69 pipeline agents that are in pivotal clinical development, in addition to the vast number of pivotal trials ongoing as part of lifecycle management (LCM) for launched oncology products. Here, we take a sneak peek focused on some of the late-stage drugs in development in the oncology pipeline.

In our analysis, over one-half of oncology pipeline agents possess novel mechanisms of action (MOA) and are vying to be first-in-class. Perhaps not surprisingly, the vast majority of these agents currently seeking first market entry are only being evaluated in one pivotal study (Figure 1). One-quarter of these pipeline agents are, however, being studied in multiple phase III trials (predominantly targeting multiple tumor types), with these multiple trials initiated before definitively established activity in patients.

Figure 2. Agents in Pivotal Trials,

by Market Size

Source: Kantar Health

It’s worthwhile to note that these pipeline compounds are nearly equally being developed by “Big Pharma” and “Small Biotechs,” with only a handful in development by Midsize/ Emerging Pharma or as a collaborative effort. However, pipeline agents with multiple pivotal trials ongoing are heavily weighted toward those in development by Big Pharma or as part of a collaborative effort. Conversely, those agents with a single pivotal trial ongoing, trend toward those in development by smaller biotechs; this potentially reflects limited resources for R&D, especially considering that the mechanisms of action of two-thirds of these agents have the potential to support development in multiple indications.

Interestingly, the majority of the indications in which these 69 agents are being developed target rather small indications in terms of patient population size. As Figure 2 shows, 60% of the ongoing pivotal trials are being conducted in indications with a target population of less than 12,500 patients.1 This is in contrast to a decade ago, when most agents in pivotal development were targeting the largest patient populations, such as breast cancer, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC).

Figure 3. Agents in Pivotal Trials,

by Unmet Need

Source: Kantar Health

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.

Some of the smaller indications represent tumors in which the incidence of the disease overall is rather small, such as acute lymphocytic leukemia (ALL) and soft tissue sarcoma, whereas others represent biomarker subsets of larger tumor types, such as Met+ NSCLC or NRAS mutant melanoma. 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. Two-thirds of ongoing pivotal studies with pipeline agents are being conducted in indications with relatively low unmet need (Figure 3).

Of course, all cancer indications have rather high unmet need compared to 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.

Through extensive analysis based on a combination of product and indication attributes, 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. Our analysis identified the Top 10 pipeline agents with the greatest potential for impact on the oncology market (Table 1 on Page 1).

1. Dabrafenib + Trametinib

Separately, 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.For metastatic melanoma, 2011 was a transformative year with the approval of Yervoy (Bristol-Myers Squibb) and Zelboraf (Genentech/Roche). Glaxo- SmithKline is developing the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib as challengers to Zelboraf’s foothold as the new standard of care in 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 randomized phase II data reported at the 2012 European Society for Medical Oncology (ESMO) annual meeting (Long, Abstract LBA27), the combination significantly prolonged progression- free survival (PFS) compared with dabrafenib alone (9.4 months vs 5.8 months; HR = 0.39; P<0.0001) while also reducing the incidence of key toxicities associated with this class of agents. These data are currently being explored in two phase III trials, evaluating the combination of dabrafenib plus trametinib in first-line metastatic melanoma, and in the adjuvant setting for patients with stage III disease.

2. Ibrutinib

The FDA approved each agent as a monotherapy in late May of 2013, but Kantar Health anticipates that 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. With the poor prognosis of patients with BRAF-mutant melanoma, the strong phase II data that nearly doubles the PFS for these patients, and the biologic potential to expand into other indications, this combination can be viewed as a regimen with breakthrough potential.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). Interestingly, ibrutinib activity does not seem to be dependent upon prior therapies or poor-risk features that typically produce varied results with other treatments. As a single agent, it produced response rates in 68% of treatment-naïve patients and in 71% of relapsed/refractory and high-risk patients with CLL (Byrd, Abstract 189, ASH 2012).

3. Idelalisib

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. With robust clinical activity and a favorable safety profile, ibrutinib makes Kantar Health’s list of potential breakthrough agents to watch.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 its clinical data was first reported at ASH 2011, showing a high response rate and PFS achieved in heavily pretreated CLL and non- Hodgkin’s lymphoma (NHL) (Coutre, Abstract 6631, ASCO 2011; de Vos, Abstract 2699, ASH 2011).

In CLL, idelalisib in combination with rituximab (Rituxan; Genentech/Roche) and/or bendamustine (Treanda; Teva) produced response rates in the range of 78% to 87% in patients who had received a median of three prior therapies, which is impressive activity compared with historical standards in this setting. Further follow-up of these studies continues to support the hype. 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.

4. Nivolumab

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. In CLL, idelalisib will compete strongly with ibrutinib, as they are both being developed in nearly identical clinical studies, so the commercial success of each agent will depend in part on the success of the other. Although limited data are available on idelalisib, the strong clinical efficacy that has been observed, coupled with the promise of PI3K inhibition gives this agent breakthrough potential.One of the hottest topics at the 2012 American Society of Clinical Oncology (ASCO) annual meeting was the role of PD-1 in suppression of antitumor immunity, most notably captured in the results of a large first-in-human phase I trial of nivolumab (Bristol-Myers Squibb). These data have been discussed at length previously, but the short story is that nivolumab demonstrated impressive activity, with durable objective responses observed in several solid tumors. The level of activity was so exciting, based largely on the fact that they were achieved with a single-agent immunotherapeutic in patients with heavily pretreated disease.

Preliminary data also suggest that PD-L1 expression may serve as a biomarker to select patients for response to nivolumab, which could further increase its efficacy in a selected population. On top of these efficacy outcomes, nivolumab impressed with its rather tolerable safety profile. From this single (albeit large) phase I trial, Bristol-Myers Squibb plowed ahead, initiating five phase III trials in three tumor types (melanoma, NSCLC, and renal cell carcinoma—the three indications with strongest efficacy signals in phase I). Such a quick move from phase I to phase III is not always advised, but it has been successful for several other agents in recent years (eg, Xalkori [Pfizer] in ALK+ NSCLC).

5. Palbociclib (PD-0332991)

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.PD-0332991 (palbociclib; Pfizer) wowed the audience at the 2012 San Antonio Breast Cancer Symposium (SABCS) annual meeting with its Kaplan-Meier curve for PFS in a randomized phase II trial of letrozole with or without PD-0332991 as first-line therapy for ER+ metastatic breast cancer. At the median, the addition of PD-0332991 increased PFS by 18.6 months, with an overall 63% reduction in the risk of progression or death (Finn, Abstract S1-6, SABCS 2012).

The drug was associated with significant hematologic toxicity, which appeared all the more significant when considered in the space of hormone therapy for breast cancer that has very few serious adverse events. While this high level of toxicity might have raised concerns, the ability to manage these toxicities through supportive care measures keeps the excitement level for this agent from being downgraded.

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 (eg, dinaciclib [Merck] is a CDK-1/2/5/9 inhibitor being studied in CLL). Although currently in pivotal development only for metastatic breast cancer, the eventual development of this regimen 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.

Table 1. Pipeline Agents with the Greatest Potential Impact in Oncology

Drug in Development





Melanoma, NSCLC


Pharmacyclics/ Johnson & Johnson

Chronic lymphocytic leukemia, mantle cell leukemia


Bristol-Myers Squibb

Melanoma, NSCLC, renal cell carcinoma



Gastric, NSCLC


Eli Lilly

Breast, colorectal, gastric, hepatoceullular carcinoma, NSCLC





ArQule/ Daiichi Sankyo

Hepatocellular carcinoma

Dabrafenib + Trametinib



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


1. Kantar Health, CancerMPact® Patient Metrics, U.S., Accessed March 25, 2013

About the Author

Stephanie Hawthorne, PhD, is Director, Clinical and Scientific Assessment at Kantar Health.

Kantar Health is a leading global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies. It combines evidence-based research capabilities with deep scientific, therapeutic and clinical knowledge, commercial development know-how, and marketing expertise to help clients launch products and differentiate their brands in the marketplace.

Kantar Health’s oncology-related offers include the CancerMPact® Future Trends and Insights module, which explores potential changes in treatment practices in the U.S., Western Europe, and Japan based on a critical evaluation of recently published clinical data, regulatory advances/ setbacks, and ongoing clinical trials.

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