The hottest PK between PD-1/PD-L1 antibodies immunotherapy

The immunotherapy is undoubtedly the hot field that has attracted the most attention of the industry in recent years. The PD-1/PD-L1 pathway antibody and CAR T-cell immunotherapy have brought amazing progress to the tumor control. The world’s first CAR T-cell product, namely, Novartis’ CAR-T therapy Tisagenlecleucel (CTL-019) was unanimously recommended by the FDA advisory committee some time ago, and the approval for the BLA of Tisagenlecleucel can be expected soon. Also, the progress in the PD-1/PD-L1 pathway antibody field is also quite eye-catching: Opdivo has been completed the key indication expansion, AstraZeneca has experienced "mixed feelings", while Keytruda has unfortunately failed in the latest Phase III clinical trial of head and neck squamous cell carcinoma. In the followings, I will update the latest situation of the PD-1/PD-L1 antibody market with you.

I. The PD-1/PD-L1 antibody market dominated by Keytruda and Opdivo: "battle of the heroic duo"

There have been 5 PD-1/PD-L1 pathway antibodies marketed so far, however, in my opinion, the PD-1/PD-L1 antibody market is still dominated by Opdivo and Keytruda, with the competition of the two progressively escalated. Overall, the PD-1/PD-L1 antibody market is rapidly growing in the volume, reaching USD 1.6 billion in 2015, USD 5.4 billion in 2016, and expected to reach USD 8.5 billion in 2017, in which, Opdivo and Keytruda are undoubtedly the strongest growth drivers of the PD-1/PD-L1 antibody market, both accounting for 95% of the market share in total, with absolute advantages. According to the authoritative forecast of Globaldata, the annual sales of Keytruda will surpass that of Opdivo in 2018 to become the best-selling PD-1/PD-L1 drug in the market. I have compared Keytruda and Opdivo in previous relevant articles, summarized into the following aspects:

1. The first mover advantages of Opdivo are the many indications and no consideration of PD-L1 expression level in the second-line treatment of non-small cell lung cancer (NSCLC). Its performance grew by leaps and bounds after it was approved, with the market share reaching 71% in 2016. In addition, Opdivo has been conducted rigorous and comprehensive patent portfolio by centering on PD-1 antibody, and won in the PD-1 patent fight to obtain a large amount of patent royalty and a share from sales for 10 years.

2. Keytruda has significant advantages in the lung cancer field. The KEYNOTE-021 pivotal trial demonstrated that Keytruda in combination with pemetrexed and carboplatin could improve the objective response rate and progression-free survival, which would make the future market expectations of Keytruda more positive. It must be particularly pointed out that Keytruda has been approved to be used for MSI-H/dMMR adult and pediatric patients with solid tumors, which is a very crucial indication. After the gap of market performance of Keytrua and Opdivo narrowed in 2017Q1 for the first time, the gap will undoubtedly further narrow, however, Keytruda will not have an overwhelming advantage over Opdivo.

II. Key indication expansion completed for Opdivo recently

According to the Q2 financial report of 2017 fiscal year recently issued by BMS, sales of Opdivo was in recession in 2017Q1 and Q2, and declined compared to 2016Q4, with the gap with Keytruda’s performance gradually narrowing. BMS officially announced on August 1, 2017 that FDA had granted accelerated approval to Opdivo injection for intravenous use for the treatment of adult or pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, upon the excellent clinical data of CheckMate-142: among patients who received treatment, the overall response rate (ORR) reached 32% and 30% patients experienced a partial response, which were exciting results to this indication. The acquisition of this indication makes Opdivo become the second "broad-spectrum oncology drug" following Keytruda, and the approval received for the indication of the drug further shows the enormous potential of immunotherapy in tumor clinical control. The clinical results are as shown in the following table:

III. "Mixed feelings" of AstraZeneca

AstraZeneca strongly joined the "PD-1/PD-L1 antibody" club upon Imfinzi, however, its market share is limited, with only the indication of urothelial carcinoma. There has been progress of Imfinzi recently, but with mixed feelings: 1. The grief is that the PD-L1/ CTLA4 combined therapy unfortunately failed in the Phase III clinical trial Mystic because it did not improve PFS, which makes people pay attention to the advantages of the PD-1 antibody and PD-L1 antibody and makes PFS possibly subject to more challenges as a lung cancer curative effect index; 2. The joy is that the interim results from the Phase III PACIFIC trial of Imfinzi were pleasantly surprising, based on which, FDA granted the breakthrough therapy designation to Imfinzi (durvalumab) for the treatment of patients with early non-metastatic NSCLC whose disease has not progressed following standard platinum-based chemoradiation therapy.

IV. Keytruda that experienced a losing streak

The momentum of Keytruda has been fiery recently, with the performance sailing with the wind, and the gap with Opvido continuously narrowing; its advantage in the lung cancer field has been unshakable, and it has opened the brand-new era of the "broad-spectrum oncology drug", however, the development of Keytruda has not been quite smooth recently: 1. The two Phase III clinical trials of Keynote-183 and Keynote-185 were halted because more patients died in the groups that received Keytruda as a treatment for multiple myeloma, compared to the control group; 2. Keytruda failed to significantly improve the patients’ overall survival in the Phase III clinical trial Keynote-040 for second-line treatment of head and neck cancer; Keytruda was originally approved to be used for head and neck cancer upon the surrogate endpoint of Keynote-040, and the above trial results brought more uncertainties to this label.

In fact, many PD-1/PD-L1 antibodies showed bug in Phase III confirmatory trials, such as Checkmate-026 and CheckMate-143 of Opdivo, and IMvigor211 of Tecentriq, which makes people question FDA’s standard of approving drugs upon surrogate endpoints.

Attached table: List of indications of PD-1/PD-L1 antibodies