20140702-高盛-Cancer_immunotherapy_primer_18页_376kb

Summary of Cancer Immunotherapy in Pharmaceuticals

Core Content

Cancer immunotherapy has emerged as a transformative approach in oncology, particularly through the use of immune checkpoint inhibitors such as Yervoy (anti-CTLA4) and PD-1/PD-L1 antibodies. These therapies work by re-training the immune system to recognize and attack cancer cells rather than directly targeting the cancer itself. The results from clinical trials, especially those presented at ASCO 2013, have demonstrated significant potential for long-term survival and durable responses, even in previously difficult-to-treat cancers like melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).

Main Points

• Mechanism of Action: Immunotherapy agents stimulate the immune system to attack cancer cells. Unlike traditional chemotherapy and targeted therapy, which kill cancer cells directly or disrupt their growth mechanisms, immunotherapy enhances immune response through checkpoint inhibition.

• PD-1/PD-L1 Inhibitors: These agents block the interaction between PD-1 and its ligands (PD-L1 and PD-L2), preventing the suppression of T-cells. They are broadly expressed on immune cells, enabling them to inhibit both cellular and antibody-mediated immunity. PD-1 inhibitors have shown activity across a wide range of tumor types, including both immunogenic and non-immunogenic cancers.

• Yervoy (anti-CTLA4): Yervoy enhances immune response by blocking CTLA4, which is involved in early immune suppression. It has demonstrated improved survival in advanced melanoma, with 5-year survival rates around 20%. However, it is associated with significant side effects, including gastrointestinal and skin toxicities, as well as pneumonitis.

• Combination Therapies: Combinations of PD-1 and anti-CTLA4 agents (e.g., nivolumab + Yervoy) have shown greater efficacy than monotherapy, with higher overall response rates (ORR) and improved long-term survival. These combinations may represent the next frontier in cancer treatment, with potential for broader application across tumor types.

• Biomarkers: While PD-L1 status is a marker for response, it is not reliable. Patients with PD-L1 negative tumors can still respond to therapy, indicating that biomarkers should not be the sole determinant of treatment eligibility.

• Market Potential: The market for cancer immunotherapy is expected to grow significantly, with initial projections for PD-1/PD-L1 agents in lung, renal, and melanoma cancers reaching $10–15 billion. The potential for first-line use across multiple cancer types is being explored.

• Safety Concerns: Immune-related adverse events, such as pneumonitis, are a concern with PD-1/PD-L1 therapies. However, these events are manageable with corticosteroids and early detection.

• Current Treatment Regimens: Traditional treatments for NSCLC, melanoma, and RCC include chemotherapy (e.g., Alimta, Taxotere), targeted therapies (e.g., Zelboraf, Sutent), and immunotherapies (e.g., Yervoy, Avastin). Immunotherapy has shown superior long-term survival compared to these other modalities.

Key Information

• BMY (Bristol-Myers Squibb) is strategically positioned with Yervoy on the market and a strong pipeline of PD-1 and other immunotherapy agents, including nivolumab, lirilumab, Urelumab, and denenicokin.

• MRK (Merck & Co.) has developed lambrolizumab (PD-1), which has shown strong single-agent activity but lacks combination potential.

• ROG (Roche) is developing MPDL3280A (PD-L1), which has a better safety profile with regard to pneumonitis.

• AZN (AstraZeneca) is also developing MEDI4736 (PD-L1), which is expected to have a significant impact in the market.

What to Watch For

• Phase 3 trials: BMY is expected to report results for nivolumab in metastatic melanoma and NSCLC by late 2014 and early 2015.

• Combination studies: The success of nivolumab + Yervoy in melanoma suggests that similar combinations could be effective in other cancers, including NSCLC and RCC.

• Safety data: Continued monitoring of immune-related adverse events, especially pneumonitis, is critical as these therapies become more widely used.

Current Estimates

• BMY: Yervoy sales are expected to grow from $969 million in 2013 to $1.86 billion by 2018. Nivolumab sales are projected to reach $3.15 billion by 2018.

• MRK: Lambrolizumab sales are expected to reach $1,000 million by 2018.

• ROG: No sales contribution is currently included in base case estimates for PD-L1.

Glossary

• Immunotherapy: Treatment that stimulates, enhances, or restores the immune system's ability to fight cancer.

• Chemotherapy: Treatment using toxic drugs to kill rapidly dividing cells.

• Targeted Therapy: Treatment using molecules that target specific proteins or interactions in cancer cells.

• Overall Response Rate (ORR): Percentage of patients whose tumors shrink or disappear after treatment.

• Progression-Free Survival (PFS): Time from treatment start until disease progression or death.

• Overall Survival (OS): Time from treatment start until death.

• Pneumonitis: Inflammation of lung tissue, a potential side effect of immunotherapy.

Disclosure

Goldman Sachs & Co. and its affiliates may have conflicts of interest due to business relationships with companies covered in this report. Investors should consider this report as one factor in their investment decisions. For full disclosure, refer to the Disclosure Appendix.