Global Tumor Immunotherapy Market Projected to Reach $60 Billion by 2025, Driven by PD-1, PD-L1, and CTLA-4 Blockade Therapies

May 31, 2016 08:00 CST Updated 08:00

Recently, CICC released a series of research reports on the field of biotech innovation. VCBeat has selected four of these reports and summarized their key insights. Below is the content of the first report.

The principle of tumor immunotherapy is to apply immunological methods to enhance the immunogenicity of tumor cells, stimulate and augment the body’s anti-tumor immune response, thereby inhibiting tumor growth. Tumor immunotherapy holds promise as a revolutionary advancement in the field of oncology, following surgery, chemotherapy, radiotherapy, and targeted therapy.

Hot targets for tumor immunotherapy include PD-1, PD-L1, and CTLA-4. In 2011, the anti-CTLA-4 monoclonal antibody Yervoy was approved by the U.S. FDA for second-line treatment of advanced melanoma, marking the advent of the era of tumor immunotherapy.

In late 2014 and 2015, PD-1 monoclonal antibodies were successively approved for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma, propelling immunotherapy to the forefront of oncology. In the future, with the approval of new indications and advancements in the development of PD-L1 monoclonal antibodies, cancer immunotherapy is poised to account for half of all cancer treatments.

$60 Billion Market Opportunity

Currently, PD-1 inhibitors have been approved for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma, with clinical trials for other indications ongoing. The market size for PD-1 monoclonal antibodies is projected to reach $35.8 billion by 2025. As no PD-L1 inhibitors have yet been launched on the market, their market size upon commercialization is estimated to be approximately 30% of that of PD-1 monoclonal antibodies.

By 2025, the market size for PD-L1 inhibitors is projected to reach $10.7 billion. CTLA-4 monotherapy and its combination with PD-1 inhibitors have also demonstrated favorable clinical outcomes in oncology, with CTLA-4 sales expected to account for 37% of PD-1 sales. By 2025, global sales of CTLA-4 monoclonal antibodies are anticipated to reach $13.3 billion. Furthermore, the combined market size for these three targeted therapies is expected to reach $59.8 billion by 2025.

Market Size Forecast for Immunotherapy Monoclonal Antibodies (PD-1 + PD-L1 + CTLA-4) from 2015 to 2025

Breakthrough in Immune Checkpoints—PD-1

PD-1 Monoclonal Antibodies—The Stars of Tumor ImmunotherapyPD-1 stands for Programmed Cell Death Protein 1. When PD-1 on lymphocytes binds to its corresponding ligands, PD-L1 and PD-L2, it inhibits lymphocyte activation. This is a normal homeostatic mechanism of the immune system, as excessive T-cell activation can lead to autoimmune diseases.

When PD-L1 on tumor cells extensively binds to PD-1 on lymphocytes, it inhibits T-cell function, allowing tumors to evade immune clearance in the body. The mechanism of action of anti-PD-1 monoclonal antibodies is to block the binding between PD-1 and its ligand PD-L1 in the body, thereby restoring normal T-cell function and enabling the immune system to eliminate tumor cells.

Mechanism of Action of PD-1 Monoclonal Antibodies

Fierce Competition in Overseas R&D of PD-1 Monoclonal Antibodies

Other foreign companies are also engaged in the competitive development of PD-1 monoclonal antibodies. CureTech and Teva are collaborating on the development of a new drug, pidilizumab (a humanized anti-PD-1 monoclonal antibody). Amplimmune is developing MEDI0680 (AMP-514), an anti-PD-1 monoclonal antibody indicated for certain solid tumors.

Meanwhile, Hengrui reached an agreement with Incyte in the United States to license its PD-1 monoclonal antibody project, which features independent intellectual property rights, to Incyte for a fee. Incyte paid Hengrui Pharma an upfront payment of $25 million and milestone payments totaling $770 million.

On October 12, 2015, Innovent Biologics and Eli Lilly reached a global development and collaboration agreement on three PD-1 bispecific antibodies, with total milestone payments exceeding $1 billion. BeiGene’s fully human anti-PD-1 monoclonal antibody entered overseas Phase I clinical trials in Australia, enrolling its first patient on June 5, 2015.

Domestic Progress of PD-1 in Development

PD-1 Clinical Trial Data—Broad Indications and Significant Efficacy

Clinical Data on PD-1 in Melanoma: PD-1 has been approved for the treatment of advanced melanoma. Compared with conventional chemotherapy, PD-1 inhibitors demonstrate a higher objective response rate (30%–40%) than conventional chemotherapy (10%–30%). Furthermore, unlike BRAF-targeted therapies, which are limited to patients with specific BRAF mutations, PD-1 inhibitors have a broader indication population.

Clinical Data on PD-1 in Non-Small Cell Lung Cancer: PD-1 inhibitors have been approved for second- and third-line treatment of non-small cell lung cancer, with an objective response rate of 16%–20%, reaching up to 40% with Keytruda in PD-L1-positive patients. Patients who have failed first-line therapy may receive PD-1 inhibitors as second-line treatment.

Comparison of Clinical Data on Different First-Line Treatment Regimens for Advanced Melanoma

PD-1 Combination Therapy—Immune Cocktail Therapies Ignite Industry Growth Points

PD-1 inhibitors are disruptive agents in cancer therapy. Their efficacy as monotherapy has been clinically validated in melanoma, non-small cell lung cancer, and renal cell carcinoma, particularly achieving high response rates in PD-L1-positive patients. The optimal strategy involves combining them with other immune checkpoint inhibitors to enhance the efficacy of immunotherapy through a multi-pronged approach.

Combination of PD-1 and CTLA-4 inhibitors. Bristol-Myers Squibb’s drug combination Opdivo + Yervoy has been approved for the second- and third-line treatment of melanoma with specific mutations, and is expected to gain approval for first-line treatment of advanced melanoma and non-small cell lung cancer in 2016 and 2019, respectively.

Combination of PD-1 and Rituximab. The novel drug pidilizumab (an anti-PD-1 monoclonal antibody), jointly developed by CureTech and Teva, in combination with rituximab, has demonstrated efficacy in B-cell lymphoma and follicular lymphoma. In a Phase II clinical trial, the combination of pidilizumab and rituximab also showed therapeutic efficacy in treating relapsed follicular lymphoma.

Combination of PD-1 and IDO inhibitors. In an early-phase clinical trial, the combination of Incyte’s IDO inhibitor epacadostat and Merck’s PD-1 monoclonal antibody Keytruda demonstrated favorable efficacy and safety. Combination of PD-1 and T-VEC.

In December 2014, Amgen and Merck & Co. entered into a strategic collaboration in immuno-oncology to advance the combined use of the cancer vaccine T-VEC and the PD-1 immunotherapy Keytruda for the treatment of advanced melanoma. In June 2015, the two companies expanded their partnership to apply this immunotherapy combination to the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck, while simultaneously initiating a Phase III clinical study of the regimen in advanced melanoma.

Combination of PD-1 and CCR4 Monoclonal Antibodies. In December 2014, Bristol-Myers Squibb entered into a clinical trial collaboration agreement with Japan’s Ono Pharmaceutical and Kyowa Hakko Kirin to conduct a Phase I clinical trial evaluating the safety, tolerability, and antitumor activity of the combination therapy of Opdivo and the anti-CCR4 monoclonal antibody mogamulizumab for the treatment of advanced or metastatic solid tumors.

PD-1 Combination Therapy with Other Drugs

The PD-1 Market Has Broad Prospects

Global PD-1 Monoclonal Antibody Market Size: The PD-1 Market Will Exceed $35 Billion. PD-1 inhibitors represent a breakthrough mechanism in anticancer therapy, having demonstrated efficacy in multiple indications such as melanoma and renal cell carcinoma. This suggests that the indications for PD-1 inhibitors will continue to expand in the future, indicating significant market potential.

Based on the indications of PD-1 monoclonal antibodies and the projected market launch timelines, the market size is analyzed, with the global market for PD-1 monoclonal antibodies expected to reach $35.8 billion by 2025.

2015E–2025E Global PD-1 Market Size Forecast

Key Assumptions for Projecting the Global Market Size of PD-1

When making predictions, the market size of 11 types of cancer was considered, including melanoma, non-small cell lung cancer, and renal cancer, which are already approved indications for PD-1, as well as triple-negative breast cancer, head and neck cancer, relapsed Hodgkin lymphoma, colorectal cancer, and other cancers that are currently under investigation as potential indications for PD-1.

From 2015 to 2025, the sales revenue ratio of PD-1 inhibitors in the United States versus other regions was 3:2;

Given the U.S. health insurance coverage rate of 86.6%, the projected disease treatment penetration rate is 85%;

The proportion of patients with metastatic melanoma who received PD-1 monoclonal antibody therapy was 16% in 2015 and 40% in 2016, followed by an annual growth rate of 5% until reaching a peak of 70%;

The proportion of patients with non-small cell lung cancer (NSCLC) who selected PD-1 monoclonal antibodies as first-line treatment was 10% in 2019, increasing by 5 percentage points annually thereafter until reaching a peak of 30%;

The proportion of patients with non-small cell lung cancer (NSCLC) who selected PD-1 monoclonal antibodies for second-line treatment was 10% in 2015, followed by an annual increase of 5 percentage points until reaching a peak of 45%;

The proportion of renal cell carcinoma patients selecting PD-1 monoclonal antibodies for second-line treatment was 3% in 2015 and 15% in 2016, subsequently increasing by 5 percentage points annually until reaching a peak of 30%;

Based on clinical trial data for Opdivo, the median survival time for renal cancer patients treated with Opdivo was 25 months, the objective response rate was 25%, and the projected proportion of renal cancer patients continuing PD-1 therapy in the second year was 25%;

The proportion of patients treated with PD-1 inhibitors for other indications is estimated based on Phase I clinical trial data, with an average treatment duration of one year;

All data are derived from clinical trial data.

Proportion of PD-1 Treatment Selection for Other Indications

Market Size of PD-1 Monoclonal Antibodies in China

At its peak, the market size of PD-1 inhibitors in China reached RMB 62.5 billion, with domestically produced PD-1 inhibitors accounting for RMB 35.2 billion. Currently, no PD-1 monoclonal antibody drugs have entered the Chinese market. Opdivo has obtained approval for Phase III clinical trials in China, and Junshi Biosciences has received domestic clinical trial approval.

The projected peak sales of PD-1 inhibitors in China amount to RMB 62.5 billion, comprising RMB 27.3 billion for imported drugs and RMB 35.2 billion for domestically produced drugs. Key assumptions underlying the forecast for the peak sales market size of PD-1 inhibitors in China:

The ratio of patients selecting domestically produced PD-1 inhibitors to those selecting imported PD-1 inhibitors was 8:2;

The proportions of Chinese patients choosing PD-1 therapy for the indications of melanoma, renal cell carcinoma, triple-negative breast cancer, head and neck cancer, relapsed Hodgkin lymphoma, mismatch repair (MMR)-deficient colorectal cancer, advanced ovarian cancer, urothelial carcinoma of the bladder, advanced gastric cancer, and advanced hepatocellular carcinoma are the same as those in the United States;

The active treatment penetration rate for all indications is 70%;

Among patients with non-small cell lung cancer (NSCLC) receiving first-line treatment, the proportion treated with PD-1 inhibitors is 20%, which is lower than the 30% rate observed in the United States. This difference is attributable to the higher prevalence of EGFR-sensitizing mutations in Asian populations (50%) compared to Western countries (10%), making Chinese patients more suitable for EGFR-TKI therapy.

The proportion of patients with advanced non-small cell lung cancer (NSCLC) progressing to second-line therapy is 60%; among those receiving second-line therapy, 40% are treated with PD-1 inhibitors.

The average duration of PD-1 therapy for Chinese patients is the same as that for US patients;

The estimated actual out-of-pocket cost for imported PD-1 inhibitors in China is RMB 560,000 per year (the U.S. price is approximately USD 150,000 per year; assuming that importers set the price at 60% of the international market level through mechanisms such as patient assistance programs, taking local affordability into account); conservatively, the price of domestically produced PD-1 monoclonal antibodies is estimated at one-third that of imported drugs, amounting to RMB 180,000 per year.

Market Size Forecast for PD-1 Monoclonal Antibodies in China

Hot Immunotherapy Target—PD-L1

Principle of PD-L1 Monoclonal Antibody Immunotherapy: PD-L1 (Programmed Death-Ligand 1), also known as B7 Homolog 1 (B7-H1), is the ligand for PD-1. The mechanism of action of PD-L1 monoclonal antibodies involves binding to the PD-L1 target on tumor cells in vivo, thereby inhibiting the interaction between PD-L1 expressed by tumor cells and PD-1 on T cells. This restores the normal function of T cells, enabling them to kill tumor cells.

Differences Between PD-1 and PD-L1 Monoclonal Antibodies

R&D Status of PD-L1 Monoclonal Antibodies

As of now, no PD-L1 monoclonal antibody drugs have been approved for marketing. Companies such as Roche and AstraZeneca have products under development. Roche’s anti-PD-L1 therapeutic agent MPDL3280A (atezolizumab) has been granted Breakthrough Therapy designation by the FDA for certain cases of non-small cell lung cancer and metastatic bladder cancer.

AstraZeneca’s PD-L1 monoclonal antibody, MEDI-4736, is currently undergoing Phase III clinical trials for lung cancer and Phase II trials for colorectal cancer. In China, in addition to developing PD-1 monoclonal antibodies, Junshi Biosciences and BeiGene are also conducting preclinical studies on PD-L1 monoclonal antibodies.

Research Progress on PD-L1 Monoclonal Antibodies by Roche and AstraZeneca

PD-L1 Combination Therapy: A New Multi-Target Treatment Option

Combination of PD-L1 inhibitor and bevacizumab. In 2014, Roche conducted a small-scale clinical trial of MPDL3280A plus bevacizumab in patients with renal cell carcinoma and colorectal cancer.

Combination of PD-L1 and CTLA-4. AstraZeneca is strategically prioritizing combination regimens involving its PD-L1 inhibitor with other anticancer agents, with CEO Pascal Soriot asserting that MEDI4736 holds greater advantages in cancer combination therapy. A Phase III clinical trial evaluating this combination therapy for advanced non-small cell lung cancer is currently underway.

Combination of PD-L1 Inhibitor and T-vec. Amgen and Roche are collaborating on a Phase I clinical trial evaluating T-vec and MPDL3280A for the treatment of triple-negative breast cancer (TNBC) and colorectal cancer with liver metastases.

Future Market for PD-L1

The market size for PD-L1 monoclonal antibodies is $10.7 billion. Currently, no PD-L1 products are on the market, and the future market size is expected to be smaller than that of PD-1, for the following reasons:

PD-1 monoclonal antibodies have gained a first-mover advantage, with products already on the market to seize market share for similar indications.

In clinical trials, the required dosage of PD-L1 monoclonal antibodies is an order of magnitude higher than that of PD-1 monoclonal antibodies; therefore, the price of PD-L1 monoclonal antibodies will be higher than that of PD-1 monoclonal antibodies in the future.

In terms of expanded indications, the research progress on PD-L1 has lagged behind that of PD-1 monoclonal antibodies. Consequently, the market size for PD-L1 is projected to be approximately 30% of that for PD-1 monoclonal antibodies, reaching $10.7 billion in 2025.

Market Size Forecast for PD-L1 Monoclonal Antibodies

Another Target of Immunotherapy—CTLA-4

CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4), also known as CD152, is a transmembrane receptor on T cells. Upon binding to B7 molecules, CTLA-4 induces T-cell anergy and specifically inhibits cellular and humoral immune responses. The therapeutic mechanism in oncology involves anti-CTLA-4 monoclonal antibodies binding to the CTLA-4 target, thereby blocking signaling pathways that facilitate tumor immune evasion and stimulating the host immune system to attack tumor cells.

Schematic Diagram of the Mechanism of CTLA-4 Monoclonal Antibody in Tumor Therapy

The Future of CTLA-4: Combination Therapy Is the Way Forward. The combination of CTLA-4 and PD-1 inhibitors holds a potential market size of $13.3 billion. Given the frequent launch of new PD-1 monoclonal antibody products, which are competitors to CTLA-4 agents, and the fact that clinical studies of PD-1 monoclonal antibodies cover more than 10 indications, whereas CTLA-4 drugs are currently studied in only a few cancers such as melanoma and non-small cell lung cancer, monotherapy with CTLA-4 inhibitors will face intense competition from PD-1 monoclonal antibodies in the future.

The optimal strategy is to combine CTLA-4 inhibitors with PD-1 inhibitors, enhancing therapeutic efficacy through distinct immunotherapy targets. Assuming CTLA-4 inhibitor sales reach 37% of PD-1 inhibitor sales, the global revenue for CTLA-4 monoclonal antibodies is projected to reach $13.3 billion by 2025.

Projected Market Size and Growth Rate of CTLA-4 Monoclonal Antibodies