Since the emergence of immune surveillance theory in the late 1950s, immune checkpoint inhibitors have become a new therapeutic hotspot in the field of combating tumors. Especially in malignant tumors such as NSCLC, melanoma, renal cell carcinoma, bladder cancer, and urothelial carcinoma, checkpoint inhibitors have shown clinical effectiveness, and the FDA has approved seven immune checkpoint inhibitors for the treatment of dozens of indications.

Since the launch of the first immune checkpoint inhibitor Ipilimumab in 2011, the market share of immune checkpoint inhibitors has grown rapidly from $706 million in 2012 to $11.4 billion in 2017, accounting for about 10% of the global tumor market. Immune checkpoint inhibitors have become one of the most investment-absorbing areas of cancer treatment. The biggest challenge remained is still how to improve the clinical effectiveness and tumor response rate of these checkpoint inhibitors, and the solution lies in the combined therapy.

Due to the high heterogeneity of human tumors, in the current therapy using immune checkpoint inhibitors, high the response rate (40%-80%) have only been observed in classic Hodgkin's lymphoma, fibroproliferative melanoma, Merkel cell carcinoma, and other microsatellite-unstable cancers. But the response rate (10% to 35%) in monotherapy for solid tumors such as non-small cell lung cancer, head and neck cancer, liver cancer, urothelial carcinoma, etc., is limited. At the same time, drug resistance problems are inevitable, and there are still few patients who can achieve long-lasting effects.

In recent years, immune checkpoint inhibitors have been used in combination with other drugs to exert complementary effects on tumor killing, and overcoming I/O response rate has become one of the research hotspots in the field of tumor immunity. At present, immunoconjugate therapy strategies include immune checkpoint antibodies, chemotherapy, radiotherapy, anti-angiogenic drugs, radiotherapy and chemotherapy, and the like are prevalent.

(1) Immune checkpoint inhibitor combined with chemotherapy

The strategy of immune checkpoint inhibitor combined with chemotherapy is a classic tumor treatment strategy. At the beginning of the development of immune checkpoint inhibitors, their initial efficacy is based on the comparison of chemotherapy on patients. On May 10, 2017, the US FDA accelerated the approval of Pembrolizumab (Keytruda) combined with pemetrexed plus carboplatin for first-line treatment of patients with advanced NSCLC (non-squamous cell carcinoma). The study was based on a multicenter, open, multi-batch patient enrollment clinical study called keynote-021.

The results of the trial showed that immunotherapy combined with chemotherapy significantly improved the objective response rate (ORR, Objective Response Rate) (55% vs 29%) and prolonged progression-free survival (mPFS, median Progression-Free Survival) (13.0 months vs 8.9 months). At the same time, the exploratory analysis of high and low stratification based on PD-L1 expression was performed. The results showed that the effective rate of the experimental group and the control group were 57% and 13%, respectively, when the PD-L1 was lowly expressed (TPS<1%), while in the high expression of PD-L1 (TPS ≥ 1%), the effective rate of the experimental group and the control group were 54% and 38%, respectively, suggesting that the high or low PD-L1 expression seems to affect little on the immune combination chemotherapy.

(2) Combination of immune checkpoint inhibitors

Since the tumor escape mechanism may involve abnormal expression of multiple immune checkpoint molecules, multiple immune checkpoint inhibitors are used in combination to treat tumors for enhanced therapeutic efficacy.

The FDA has approved Opdivo+Yervoy for melanoma, advanced renal cell carcinoma, MSI-H or dMMR metastatic colorectal cancer, and the combination is used for first-line treatment of tumor mutation load (TMB) ≥10 mutations/mega Baseline (mut/Mb) patients with advanced non-small cell lung cancer (NSCLC), a Supplemental Biologics License Application (sBLA) of which has been submitted on June 24, 2018, with a scheduled review date of February 20, 2019.

(3) Immune checkpoint combined with anti-angiogenic drugs

Some experts believe that immune checkpoint inhibitors combined with anti-angiogenic drugs, especially combined with VEGF target drugs will be a research hotspot.

In January 2018, Merck's PD-1 antibody, pemizumab (Keytruda), and Eve's VEGF/FGF inhibitor levastatin were approved by FDA for combination therapy for advanced and/or metastatic renal cell carcinoma (RCC). The objective response rate of patients with combination therapy was 63.3%. In addition, the two companies will develop a combination of drugs for bladder cancer, endometrial cancer, head and neck cancer, melanoma, non-small cell lung cancer and other indications.

In addition, in August 2018, Atezolizumab combined with bevacizumab (Avastin) was approved by FDA breakthrough therapy for first-line treatment of advanced or metastatic hepatocellular carcinoma, with an objective response rate of 65%. At the same time, the PFS of Atezolizumab combined with bevacizumab (Avastin) in the first-line treatment of advanced renal cell carcinoma, and combined therapy with sunitinib for PD-L1 positive patients, were: 14.7 months and 7.8 months.

Summary

The launch of tumor immune checkpoint inhibitors is a milestone in cancer treatment. The immune checkpoint inhibitor represented by PD-(L)1 has shown good curative effect in various tumor treatments, providing better treatment options a specific ratio for specific populations. But the overall efficiency of such drugs is not high, the objective response rate of single drugs is more than 20% -30%; single drug for first-line treatment remains to be studied. Based on these limitations, combination therapy has become a hot topic of exploration, improving efficacy through the use of other therapies, while changing the first-line treatment pattern.

Currently, immunrcheckpoint inhibitors have been used in combination with each other, and combination with chemotherapy has also been shown to increase patient response rates. In the case of combined targeted drugs, although clinical studies combining EGFR and ALK mutant small molecule targeted drugs have been frustrated, immune checkpoint inhibitors combined with anti-angiogenic targeted drugs have shown clinically efficacy, when combined with other target drugs such as PARP inhibitors , MEK inhibitors, Bombesin Receptor Inhibitor, CD30 inhibitor, etc. However, combined treatment of tumors also has problems such as joint timing, dose optimization, pharmacoeconomics, side effects, etc. In the future, a more accurate understanding of the mechanism of immunotherapy and a better identification of biomarkers for clinical efficacy prediction is the key to the development of combination therapy.

Author's Bio: 

This article is written by scientists from BOC Sciences.