ASCO 2020: Genentech’s Novel anti-TIGIT Therapy Shows Promise in Phase II Lung Cancer Trials

By T. Chakraborty, Ph.D.

Tiragolumab’s encouraging data bolster the fight against lung cancer, the second most common cancer with a 5-year survival rate of 24%.

Lung cancer is one of the leading causes of cancer deaths globally and accounts for 25% of all cancer patients. So, there is an urgent need for novel therapies against this deadly disease [1]. The immune cells that protect us from external attacks, also self regulates itself by producing immune checkpoint proteins to prevent uncontrolled responses. Unfortunately, by expressing checkpoint proteins on their cell surfaces, the intelligent cancer cells bypass the immune system.

 

TIGIT Immune Receptor

Hence, in recent years, cancer immunotherapies targeting these proteins have come to the forefront of lung cancer treatment. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is one such immune checkpoint protein that has gained much attention in recent years due to the variety of roles it plays in cancer [2]. Dr. Melissa Johnson, Associate Director for Lung Cancer at Sarah Cannon Research Institute, on behalf of her co-investigators at Genentech, gave an update on a Phase II trial for anti-TIGIT therapy, Tiragolumab for patients with non small cell lung cancer (NSCLC).

 

Tiragolumab

CD8+ cytotoxic T-cells and other immune cells express TIGIT on their cell surface and inhibit the immune response by binding to its ligand, CD155 (PVR). TIGIT inhibits the inflammatory response from immune cells by competing with different receptors such as CD226, which helps mount an immune response against cancer cells.

Tiragolumab is a fully human IgG1 monoclonal antibody developed by Genentech against TIGIT. The drug binds to TIGIT and inhibits its interaction with PVR. Pre-clinical studies have shown that combination treatment of Tiragolumab with a PD-L1 inhibitor synergistically improves survival in a rodent model of cancer [3]. Further, Phase I clinical trials showed that Tiragolumab was well tolerated by study subjects as a monotherapy or combination therapy along with PD-L1 inhibitor, Atezolizumab. The complete data will be presented at the virtual AACR meeting later this summer.

 

CITYSCAPE Trial

The success of Phase I led to the start of the CITYSCAPE, a Phase II trial involving 135 patients with Stage IV NSCLC who had 1% or higher level of PD-L1 in their tumors. Among them, 67 patients received Atezolizumab plus Tiragolumab while the rest received Atezolizumab alone. The early analysis revealed that patients receiving the combination therapy had an overall response rate (ORR) of 31% as compared to 16 % with monotherapy.

Further, combination therapy improved the progression free survival (PFS) to 5.4 months versus the monotherapy’s 3.6 months. After six months of additional follow up, an updated analysis revealed that the combination therapy had a response rate of 37% and progression free survival rate of 5.5 months while the monotherapy achieved 21% and 3.9 months. Dividing the data for PD-L1 levels in the tumor, Dr. Johnson reported that patients with PD-L1 levels higher than 50% had an ORR of 66% with combination therapy as compared to only 24% in the monotherapy arm.

When the PD-L1 level is less than 50%, there was no difference between the two treatments. The number of adverse events reported was comparable between the two groups. The major events included mostly immune-related side effects. Dr. Johnson concluded that these new data have led to the recent launch of the SKYSCRAPER 01, a phase III trial for patients with more than 50% PD-L1 levels [4,5].

 

Other Competitors 

Due to the druggability of this immune checkpoint inhibitor, many other companies, including Merck, Arcus Biosciences, Bristol‐Myers Squibb, OncoMed Pharmaceuticals and Astellas Pharma are following suit to develop anti-TIGIT therapy. Merck’s MK-7684 and  MK-3475-01A Bristol‐Myers Squibb’s, BMS-986207, are also in Phase II trials. Moreover, other smaller biotech companies, like Seattle Genetics and Iteos Therapeutics, are also venturing into developing anti-TIGIT therapies. Although TIGIT looks like a great candidate for advanced cancer treatment, the data from CITYSCAPE clinical trial by Genentech reminds us to be cautiously optimistic as it might only be beneficial to a subgroup of patients [6,7].

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: ASCO 2020: Global Consortiums CCC19, and TERAVOLT Improve Understanding of Cancer and COVID-19

References
  1. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html
  2. https://www.ncbi.nlm.nih.gov/pubmed/27793572
  3. https://pubmed.ncbi.nlm.nih.gov/25465800/
  4. https://clinicaltrials.gov/ct2/show/NCT03563716
  5. https://clinicaltrials.gov/ct2/show/NCT04294810
  6. https://clinicaltrials.gov/ct2/show/NCT04256421
  7. https://geneonline.news/en/2020/04/04/tigit-immunotherapy-a-ray-of-hope-for-cancer-treatment/
  8. https://meetinglibrary.asco.org/record/184799/abstract

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