Cabozantinib

Cabozantinib EXELIXIS, INC. 2011 ANNUAL REPORT Cabozantinib a potent, first-in-class, tyrosine kinase inhibitor that simultaneously targets the MET and V EGF signaling pathways. In clinical studies, cabozantinib has demonstrated a unique spectrum of anti-tumor activity in 12 out of 13 tumor types tested, with regression of metastatic or primary tumor lesions in so t sue, v ceral organs and the brain, and resolution of bone lesions on bone scan. we initiated the fi rst of two planned pivotal trials in metastatic castration-resistant prostate cancer (CRPC) and executed an agreement with the National Cancer Institute to broadly explore tumor indications outside of MTC and CRPC. LOOKING TOWARD APPROVAL One high point of 2011 was the positive outcome of the cabozantinib pivotal phase 3 clinical trial in MTC – the fi rst time we’ve generated pivotal data for one of our compounds. With a nearly three-fold Michael M. Morrissey, Ph.D. increase in progression-free survival over placebo, the data clearly demonstrate that cabozantinib provides a substantial benefi t to MTC patients. These data offer hard evidence that cabozantinib is a potent anti- TO OUR STOCKHOLDERS cancer agent with the ability to signifi cantly improve outcomes in a patient population that has few options and represents a signifi cant unmet medical need. IF I SUM UP 2011 FOR EXELIXIS IN A SINGLE WORD, Although MTC is not a major commercial opportunity, IT IS “CLARITY” — OF OPPORTUNITY, DIRECTION, pursuing the indication has given us the ability to move AND PURPOSE. It was a year in which the unique forward with a New Drug Application (NDA) in MTC, activity profi le and broad commercial potential of providing a solid foundation upon which to build a cabozantinib became clear, and our fi rst potential franchise in prostate cancer and other tumor types. product approval came into view. By focusing our As we work to complete the rolling NDA submission resources and efforts on maximizing the value of that started in late 2011, we have established arrange- cabozantinib, we defi ned a clear path to building an ments with external manufacturers to ensure we can oncology franchise in multiple tumor indications. supply cabozantinib to patients pending regulatory Our broad, yet disciplined, development program approval. Additionally, our commercial team is building for cabozantinib advanced signifi cantly in 2011 and the distribution and customer support network that will is positioned to generate multiple opportunities for enable us to make the drug commercially available once value creation in 2012 and beyond. approved. We are proud of the many accomplishments that have allowed us to take cabozantinib from an Inves- EXELIXIS: THE CABOZANTINIB COMPANY tigational New Drug (IND) fi ling to NDA submission 2011 was the year in which cabozantinib became our in 7 years, while retaining full rights to the compound. sole focus. After seeing early but compelling clinical data in 2010, we made the strategic decision to realign CONVERTING A UNIQUE CLINICAL PROFILE INTO our resources and operations to focus exclusively on A COMMERCIALLY DIFFERENTIATED PRODUCT advancing this unique compound. We continued the Cabozantinib’s unique clinical profi le, especially its diffi cult yet necessary task of reducing our headcount ability to resolve existing metastatic bone lesions on and our real estate costs so that every aspect of our bone scan in prostate cancer and other tumor types, business aligns with our singular focus on cabozantinib. was initially documented in 2010. Throughout 2011 The value of this approach became clear in 2011 as new we further delineated this profi le and generated data data across a variety of tumor indications continued that we believe will differentiate cabozantinib in the to support the vision that cabozantinib can succeed as clinic and marketplace. This approach is refl ected in a next generation anti-tumor agent. The potential is the trajectory of our CRPC program, which garnered obvious – to date cabozantinib has shown anti-tumor signifi cant attention at the American Society of Clinical activity in 12 out of 13 tumor types tested, and has Oncology’s 2011 Annual Meeting for cabozantinib’s induced regression of metastatic or primary tumor dramatic effect on bone metastases as evidenced by lesions in soft tissue, visceral organs and the brain, and resolution of bone scans, and the association of this resolution of bone lesions on bone scan. Importantly, effect with multiple measures of clinical benefi t. We cabozantinib delivered impressive pivotal trial data were also able to document the unique bone benefi ts in medullary thyroid cancer (MTC). In addition, of cabozantinib in a variety of other tumor types, Phase 3 O Metastatic Castration-Resistant Prostate Cancer (mCRPC): COMET-2 Pain Palliation and Narcotic Reduction Trial O Medullary Thyroid Cancer: EXAM Pivotal Trial PLANNED TO START IN 2012 O mCRPC: COMET-1 Overall Survival Trial Phase 2 Randomized Discontinuation Trial O Breast Cancer O Gastric/GE Junctional Cancer O Hepatocellular Carcinoma O Melanoma EMERGING CABOZANTINIB O mCRPC ONCOLOGY FRANCHISE O Non-Small Cell Lung Cancer O Ovarian Cancer O Pancreatic Cancer O Small Cell Lung Cancer OUR LEAD COMPOUND CABOZAN- TINIB IS THE SUBJECT OF A BROAD Phase 2 Non-Randomized Expansion Cohorts CLINICAL DEVELOPMENT PROGRAM O mCRPC DESIGNED TO MAXIMIZE ITS POTEN- O Ovarian Cancer TIAL AS AN ANTI-CANCER AGENT. The program encompasses pivotal Phase 2 trials in medullary thyroid cancer and O Glioma castration-resistant prostate cancer, O Hormone-Receptor-Positive Breast Cancer with Bone Involvement (*) as well as a broad phase 2 program O Chemotherapy-naïve mCRPC (*) and multiple earlier-stage trials. The O Pancreatic Neuroendocrine and Carcinoid Tumors (*) clinical experience to date includes PLANNED TO START IN 2012 data from more than 1,500 patients. O Advanced Solid Malignancies – Evaluation of Bone Scan Response (*) O mCRPC – Evaluation of Pharmacodynamics and Response (*) ADDITIONAL PIPELINE ASSETS O Metastatic Triple-Negative Breast Cancer (*) There are 12 additional compounds O Non-Small Cell Lung Cancer (*) or programs out-licensed to partners O Advanced Solid Tumors - Bone Biomarker Evaluation (*) for which Exelixis is eligible for substantial milestones and royalties in various disease therapeutic areas, Phase 1/2 O Non-Small Cell Lung Cancer including oncology, infl ammation, cardiovascular disease and metabolic PLANNED TO START IN 2012 disease (see the Form 10-K which is part O Multiple Myeloma (*) of this Annual Report for information regarding Exelixis’ collaborations). Phase 1b O mCRPC – Combination with Abiraterone (*) O Differentiated Thyroid Cancer O Renal Cell Carcinoma PLANNED TO START IN 2012 O Androgen-Dependent Metastatic Prostate Cancer (*) O Melanoma (*) O Pancreatic Cancer (*) Phase 1 O Advanced Solid Tumors (Japan) *Denotes study executed under Exelixis’ Investigator-Sponsored Trial Program including differentiated thyroid cancer, metastatic broad activity in a variety of tumor types. In addition breast cancer, melanoma, and renal cell carcinoma. to clinical activity and benefi t observed in the melanoma, non-small cell lung cancer, and ovarian cancer We also investigated the ability of cabozantinib to cohorts of the RDT, cabozantinib was the subject of decrease pain and reduce or eliminate use of narcotic data presentations in several additional indications in medications by men with advanced CRPC. In 2011, 2011 and early 2012: our investigators generated data further supporting this aspect of the cabozantinib profi le. In particular, Metastatic Breast Cancer In December 2011, we reported investigators presented interim fi ndings from the encouraging preliminary data from the metastatic non-randomized expansion cohort in CRPC patients breast cancer cohort of the RDT. In this heavily in November which demonstrated that nearly half of pretreated population, nearly half of the patients the men with moderate-to-severe bone pain enrolled achieved a partial response or demonstrated stable in this phase 2 study reported a durable pain response. disease at Week 12. Forty percent of evaluable patients Importantly, more than half of these men were able to achieved partial resolution of their metastatic bone decrease, or in some cases discontinue outright, their lesions on bone scan, and individual patients had narcotic pain medication usage. We have incorporated improvement in their bone pain. these fi ndings into the planning process for our two Hepatocellular (Liver) Carcinoma Positive preliminary CRPC pivotal trials. data from this cohort of the RDT were presented in Taken as a whole, we believe that cabozantinib’s January 2012. The Week 12 disease control rate was potential ability to improve both overall survival and 68%, and evidence of tumor regression was observed pain, combined with its broad anti-tumor activity, in more than three quarters of patients. These are demonstrable signs of clinical benefi t as evidenced encouraging results given the advanced nature of the by bone scan response, and convenient route of disease in this patient population. administration, should position cabozantinib well for Differentiated Thyroid Cancer and Renal Cell Cancer potential success in the CRPC marketplace. We also reported encouraging preliminary data from FOCUS ON CRPC a separate clinical trial enrolling cohorts of patients with differentiated thyroid cancer (October 2011) and We are highly focused on the rapid execution of renal cell cancer (February 2012). More than half of our two pivotal studies in CRPC, COMET-1 and the differentiated thyroid cancer patients achieved COMET-2. COMET-1 will evaluate the impact of a confi rmed partial response, and all patients experi- cabozantinib versus prednisone on overall survival in enced tumor regression. The renal cell cancer cohort patients with CRPC who have progressed following was heavily pre-treated, and tumor regression was prior treatment with docetaxel and abiraterone or observed in 90% of patients. Nearly three quarters of MDV3100. COMET-1 is planned to enroll 960 patients exhibited a partial response or stable disease patients and is expected to start in the fi rst half of 2012.

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