What Will Change the Field of Oncology in 2012?

In 2011, five new agents were approved in the U.S. that transformed the field of oncology: Adcetris™ (brentuximab vedotin, Seattle Genetics), Xalkori® (crizotinib, Pfizer), Yervoy™ (ipilimumab, Bristol-Myers Squibb), Zelboraf® (vemurafenib, Roche/Plexxikon, a member of the Daiichi Sankyo group) and Zytiga® (abiraterone, Johnson & Johnson).

• Adcetris™ is an antibody-drug conjugate that delivers chemotherapy directly to CD30-expressing cells. It gained approval in relapsed Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. Its approval brought a major therapeutic advance to a tumor type that drug developers have largely ignored due to the small market size.

• Xalkori® is an ALK inhibitor that demonstrated spectacular efficacy in non-small cell lung cancer patients harboring EML4-ALK fusion. Although other ALK inhibitors have entered clinical development, none have yet reached Phase III status.

• Yervoy™ is an immunotherapeutic targeting the brake of the immune system called CTLA4. It was the first agent to demonstrate improved overall survival in a Phase III melanoma trial in 30 years. Its main drawback, however, is the immune-related adverse toxicity that requires close monitoring of the patient.

• For melanoma patients harboring BRAFV600E mutation (a key driver of the disease), the approval of Zelboraf® (an inhibitor of BRAFV600E mutant) now offers another treatment option. It demonstrated impressive efficacy, similar to that observed for EGFR mutants and EGFR inhibitors in lung cancer, and marked the beginning of personalized medicine in melanoma.

• Zytiga® is an inhibitor of an enzyme involved in testosterone production in testicular and adrenal tissue. It introduced a new treatment paradigm in prostate cancer by showing that patients previously considered hormone-resistant may still respond to endocrine therapy.

With so many advances in oncology in 2011, other drugs are filling up oncology pipelines with the promise of offering new therapeutic options for patients with unmet needs.

T315I Chronic Myelogenous Leukemia: Will Ponatinib Succeed?
Chronic myelogenous leukemia harboring the T315I mutation represents an important unmet need as it does not respond to currently approved tyrosine kinase inhibitors. Ariad’s ponatinib, a BCR-ABL inhibitor, is the most promising late-stage agent that showed encouraging data at the 2011 American Society of Hematology (ASH) annual conference. Ariad is also developing a companion diagnostic test for the detection of the T315I mutation in collaboration with MolecularMD, which will be key for its success.

KRAS Mutant Colorectal Cancer: Is Indirect Targeting the Only Way to Go?
KRAS mutant colorectal tumors do not respond to EGFR-targeted antibodies. The main problem is that although KRAS mutations are relatively common in colorectal cancer, the KRAS protein itself isn’t an easily druggable target, and all attempts to date have failed. Rather, most of the developmental focus has been on indirect targeting of KRAS through its downstream targets (such as Raf or MEK) or targeting other upstream receptor tyrosine kinases. NKTR-102 (a next generation topoisomerase I inhibitor from Nektar) is currently in Phase II/III development specifically in KRAS mutant colorectal cancer patients. Two other drugs in Phase 2/3 delopment come from Amgen’s pipeline: AMG479 (an IGF-1R antibody) and AMG655 (a TRAIL receptor 2 agonist). Efficacy data has not yet been presented, but if positive, these drugs could finally offer a personalized treatment option for patients with KRAS mutations.

MEK Inhibitors: A New Class of Drugs on the Horizon
MEK inhibitors have gained a lot of attention as potential therapy in BRAF mutant melanoma either as monotherapy or in combination with BRAF inhibitors. At least five MEK inhibitors are in clinical development, although so far GSK1120212 from GlaxoSmithKline is the only one in a Phase 3 program for melanoma harboring V600E/K mutations. If approved, it will face stiff competition from Zelboraf, which captured a significant portion of the BRAF mutant melanoma market after its 2011 launch. Combination with a BRAF mutant inhibitor could represent a better strategy in terms of both efficacy and safety, and GlaxoSmithKline is already exploring this combination approach in a Phase I trial with GSK1120212 and its BRAF inhibitor GSK2118436. Other companies have jumped in to evaluate BRAF/MEK combination, with Novartis conducting a trial with RAF265 and MEK162, and Roche/Daiichi Sankyo conducting a combination trial with Zelboraf and GDC0973.

PI3K Inhibitors: A New Class of Drugs on the Horizon
At least 16 Class I PI3K inhibitors are in clinical development, but some differentiation exists between them – some are pan-PI3K inhibitors, some are isoform-specific inhibitors and some are dual PI3K and mTOR inhibitors. Notably, several PI3K inhibitors are currently in Phase 1/2 trials in endometrial cancer: Pfizer’s PF-04691502, Novartis’ BKM120 and BEZ235, XL147 from Sanofi and Exelixis, and Daiichi’s DS-7423. This is an example of a niche indication that has not really benefited from active drug development until PI3K mutations were identified in these tumors. Several companies are also currently evaluating the combination of PI3K and MEK inhibitors. For example, Roche/Genentech is conducting a trial with GDC0941 plus GDC0973; Novartis with BKM120 plus MEK162, BEZ235 plus MEK162, and BKM120 plus GSK1120212; Pfizer with PF04691502 or PF05212384 plus PD0325901; and GlaxoSmithKline with GSK2126548 plus GSK1120212.

Refocusing Pipelines on Niche Indications
Approval of several targeted therapies over the last decade speaks to the trend that “one size fits all” oncology drugs are becoming a thing of the past. More and more companies are developing therapies for patient segments expressing a specific biomarker within a big tumor type but are also refocusing their pipelines on niche indications that have previously been largely ignored. While patient numbers are smaller, return on investment can still be attractive, especially if the agent demonstrates remarkable efficacy as seen with Xalkori® in EML4-ALK-fusion positive non-small cell lung cancer.

Sarcoma is an example of a niche indication that has enjoyed a lot of clinical activity, with several drugs in Phase III programs. The closest to approval are Votrient® (pazopanib, GlaxoSmithKline) in the refractory setting and Ariad’s ridaforolimus in the maintenance setting, both of which filed regulatory submissions in July 2011. Other drugs with active Phase 3 programs include Sanofi’s AVE8062 (a vascular disrupting agent), Ziopharm’s Zymafos™ (an active metabolite of ifosfamide that is already considered the standard of care for sarcoma), Threshold Pharmaceuticals’ TH-302 (a hypoxia-activated prodrug that releases DNA alkylating agent within hypoxic regions of tumors), Eisai’s Halaven™ (eribulin, a tubulin targeted drug already approved for breast cancer) and Yondelis® (trabectedin, PharmaMar/Johnson & Johnson).

Other drugs in late-stage development pursuing niche indications include Genentech’s Erivedge™ (vismodegib) in basal cell carcinoma and Astellas’ OSI-906 in adrenal cancer. Erivedge™ is an inhibitor of the hedgehog signaling pathway that earned regulatory approval in the U.S. in January 2012. Not surprisingly, other hedgehog inhibitors have entered clinical development, such as LDE225 (Novartis), BMS-833923 (Bristol-Myers Squibb/Exelixis), IPI-926 (Infinity Pharmaceuticals), PF-04449913 (Pfizer), LEQ506 (Novartis) and TAK-441 (Millennium/Takeda). OSI-906 is an IGF-1R and insulin receptor inhibitor and so far is the only drug in Phase III development for adrenal cancer.

Drug developers continue to invest substantial resources behind cancer drugs, and novel mechanistic classes are emerging on the horizon as potential new therapies. Some of these drugs were highlighted above, but Kantar Health’s CancerMPact® Emerging Technologies offer provides a detailed, unbiased evaluation of the overall commercial viability of more than 50 of the most promising cancer agents as well as emerging mechanisms of action in clinical development that will have a significant commercial impact in the next five years. If you would like more information about this offer, please contact us at www.kantarhealth.com/contactus or email info@kantarhealth.com.

By Tatiana Spicakova, PhD, Associate Consultant, Kantar Health

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