Global Oncology Leaders Enter the TIGIT Arena as Tiragolumab Shines in Phase III Trials

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Recently, Roche’s TIGIT monoclonal antibody, tiragolumab, registered a highly anticipated Phase 3 clinical trial (NCT04513925) on ClinicalTrials.gov. The trial targets consolidation therapy for unresectable Stage III non-small cell lung cancer (NSCLC), marking an aggressive challenge by the atezolizumab–tiragolumab combination against durvalumab in its dominant indication. This is the fourth “skyscraper” project initiated for tiragolumab, codenamed SKYSCRAPER-03.

SKYSCRAPER-03:

Atezolizumab + Tiragolumab vs. Durvalumab

Source: https://clinicaltrials.gov/ct2/show/NCT04513925

According to publicly available information, tiragolumab has successively initiated four pivotal Phase IV clinical trials to date: first-line treatment for non-small cell lung cancer (NSCLC), first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), consolidation therapy for Stage III NSCLC, and cervical cancer. All of these trials warrant special attention. Notably, the most recently registered trial is a head-to-head study against durvalumab in its approved indications. Whether Roche can achieve a breakthrough from the ground up remains to be seen as developments unfold.

“Tumor Immunotherapy” Ushers in an Era of Unified Cancer Treatment

As the saying goes, “what is united for long must divide, and what is divided for long must unite.” The PD-(L)1 pathway is a rare and legendary therapeutic target. PD-(L)1 monoclonal antibodies, represented by Opdivo and Keytruda, have ushered in the era of “tumor immunotherapy,” which marks a grand unification in cancer treatment and will long serve as the cornerstone of therapy for multiple types of tumors.

The clinical benefits and limitations of PD-(L)1 monoclonal antibodies are already evident. Undoubtedly, in the post-PD-(L)1 monoclonal antibody era:

• PD-(L)1 inhibitors will continue to explore adjuvant or neoadjuvant treatment regimens in patients with early-stage cancer; whether another legend can be created remains to be seen—stay tuned.
• PD-(L)1 monoclonal antibody combination therapies continue to attract widespread attention, aiming to further enhance clinical benefits;
• Following PD-(L)1, Who Will Be the Successor to Immune Checkpoints? This Is Also a Widely Discussed Question.

Multiple Global TIGIT Programs Expected to Accelerate

In 2020, TIGIT ushered in its first wave of spotlight moments.

In the first quarter of 2020, Roche initiated two pivotal Phase III clinical trials listed on ClinicalTrials.gov, targeting first-line indications for lung cancer. At the 2020 ASCO Annual Meeting, tiragolumab made a remarkable debut: the combination of atezolizumab and tiragolumab significantly improved the objective response rate and clinical benefit in patients with PD-L1-high non-small cell lung cancer (NSCLC).

https://www.roche.com/dam/jcr:6581a61d-c326-4708-a376-6780b2735e5d/en/irp200723.pdf

Insights from the 2020 ASCO Data on Tiragolumab:

• The objective response rate (ORR) of tiragolumab monotherapy was very low (AACR 2020, Abstract CT302), indicating that tiragolumab must be combined with a PD-(L)1 monoclonal antibody. Therefore, follow-on developers must also have a PD-(L)1 monoclonal antibody in their portfolio.
• Combination Therapy vs. PD-(L)1 Monoclonal Antibodies: The Improvement in Objective Response Is Clear, with ORR Doubling, Which Is a Definitive Signal;
• The use of combination therapy should be limited to the population with high PD-L1 expression.

Based on this, interest in TIGIT surged after May 2020, making it the most closely watched immune checkpoint following PD-(L)1 and CTLA-4. Several related advances can be noted:

• On May 14, Boehringer Ingelheim acquired Northern Biologics, most likely attracted by its TIGIT monoclonal antibody;
• On May 27, Gilead and Arcus Biosciences established a 10-year long-term collaboration and development agreement, with Arcus’s PD-1 monoclonal antibody zimberelimab and TIGIT monoclonal antibody AB154 drawing significant attention;
• On June 9, BeiGene explicitly stated at an investor conference that the TIGIT program would be accelerated.
• Following Roche, TIGIT projects are undoubtedly blossoming everywhere.

Globally, in the landscape of TIGIT monoclonal antibodies, top-tier global immuno-oncology leaders such as Roche, Merck & Co., and Bristol Myers Squibb have all entered the field, with Roche taking the lead; among China’s top-tier immuno-oncology companies, BeiGene, Innovent Biologics, Junshi Biosciences, and Hengrui Medicine have all entered the market, with BeiGene leading.

Challenging AstraZeneca's "Pacific Storm"

Among the various PD-(L)1 monoclonal antibodies, AstraZeneca’s durvalumab has a unique indication: as a consolidation therapy for patients with unresectable, locally advanced stage III non-small cell lung cancer (NSCLC), both squamous and non-squamous histologies, whose disease has remained stable following chemoradiotherapy. It is precisely this differentiated indication that has driven the robust growth of durvalumab.

Durvalumab avoided fierce competition in the indication for stage IV lung cancer by taking an alternative approach, targeting stage III non-small cell lung cancer (NSCLC). In 2014, a phase 3 clinical trial focused on early-stage lung cancer was initiated, known as PACIFIC (NCT02125461). Robust data from the PACIFIC trial supported durvalumab’s approval as a new consolidation therapy for stage III NSCLC.

The SKYSCRAPER-03 pivotal Phase 3 trial has thus become highly noteworthy, as it features a head-to-head challenge of atezolizumab combined with tiragolumab against durvalumab, aiming to upgrade or pioneer consolidative therapy for Stage III non-small cell lung cancer (NSCLC) patients. This represents a significant breakthrough from the ground up; whether Roche succeeds remains to be seen in future developments.

The Competitive Threshold in the “Post-PD-(L)1 Era” Will Be Raised

PD-(L)1 monoclonal antibodies represent the pinnacle of tumor immunotherapy. These agents have brought about a landmark transformation in the treatment paradigms for various solid tumors, including lung cancer, hepatocellular carcinoma, and melanoma. It is no exaggeration to state that PD-(L)1 inhibitors have ushered in a new era. To date, global sales of PD-(L)1 monoclonal antibodies have approached $30 billion, with Keytruda dominating the market and accounting for nearly 50% of total sales.

Currently, with the exception of the final stronghold—early-stage adjuvant or neoadjuvant therapy—the disease landscape for PD-(L)1 monoclonal antibodies is nearly fixed. We are gradually entering the “post-PD-(L)1 era,” where the threshold for competitive dynamics is significantly higher; therefore, competition in the “post-PD-(L)1 era” may:

• Resistance to PD-(L)1 monoclonal antibodies will become a key area of development, either by pursuing combination therapies or exploring other novel approaches;
• The development of novel immune checkpoint inhibitors remains a challenging frontier, with many molecular mechanisms yet to be elucidated; therefore, the discovery of entirely new immune checkpoint drugs will continue to be a significant direction, although another blockbuster akin to PD-(L)1 inhibitors is unlikely to emerge.
• PD-(L)1 monoclonal antibody-based combination therapies are expected to constitute a long-term landscape in future oncology treatment. Consequently, this trend significantly benefits holders of PD-(L)1 monoclonal antibodies while substantially constraining those without such assets, thereby accelerating the elevation of competitive barriers.
• “Unity leads to division, and division leads to unity.” In the future, oncology treatment regimens will continue to evolve toward precise patient stratification.
• New-generation CTLA-4 monoclonal antibodies, TIGIT monoclonal antibodies, and Siglec-15 monoclonal antibodies are currently hot areas of focus.