TIGIT Revelation: The Indomitable PD-1 and the Perilous Path of Innovation

TIGIT Track: Transaction Amount Exceeds $6 Billion

GSK, BMS, Merck, Novartis, Gilead and other Big Pharma have placed huge "bets", while leading domestic Biotechs such as BeiGene, Junshi, and Innovent are catching up.

However, the recent consecutive setbacks of Roche's "PD-L1+TIGIT" combination therapy have cast a shadow over pharmaceutical companies in this field, as this rapidly rising target is experiencing unprecedented challenges.

Why Roche's Clinical Trials Failed to Meet Expectations? And Where is TIGIT's Chance for a Comeback?

TIGIT has become a star molecule because, when combined with anti-PD-L1 therapies (such as Tecentriq), it can simultaneously prevent or reverse the exhaustion of T cells and NK cells. It was once regarded as the future of immunotherapy, with some even calling it "the next PD-1."

As the leader in the TIGIT field, Roche has heavily invested in the combination therapy of PD-L1 antibody Tecentriq and TIGIT antibody Tiragolumab, having already initiated 9 pivotal clinical trials. Tiragolumab is also considered the most promising product in the TIGIT field, demonstrating excellent performance in Phase II clinical studies.

However, the higher you捧, the harder you摔.

Tiragolumab+Tecentriq: This combination therapy has encountered significant challenges in two clinical trials for the treatment of lung cancer.

In March 2022, the Phase III clinical trial of the combination therapy for small cell lung cancer (SCLC) was declared a failure, as both primary endpoints, PFS (Progression-Free Survival) and OS (Overall Survival), were not met. In May, interim data from the Phase III clinical trial for first-line treatment of non-small cell lung cancer (NSCLC) showed that the primary endpoint of PFS was not achieved.

This stands in stark contrast to the previously positive results from Phase II clinical trials. If the clinical trial targeting small cell lung cancer was merely Roche's initial exploration, with data outcomes not generating much expectation, then given Tecentriq's remarkable efficacy in treating non-small cell lung cancer, the failure of combination therapy for this indication has truly made those following the TIGIT track sense a crisis.

Why Did Roche Fail?

The problem may lie in the most fundamental mechanism环节.A senior industry insider specializing in antibody drugs told VCBeat that the potent efficacy of PD-(L)1 might have overshadowed the therapeutic effectiveness of TIGIT. When both therapies aim to kill tumor cells by activating T cells, they may not produce a 1+1>2 effect. "It's like scoring 99 on an exam and then saying you want to study more to see if you can get 100. That’s very difficult."

Overly positive results from animal experiments may have inflated expectations for TIGIT.An industry insider who once participated in TIGIT target research told VCBeat New Medicine that the expression of TIGIT in animals and humans may have some differences, which could lead to discrepancies between preclinical and clinical data.

In addition, entering Phase III clinical trials, the increase in the number of enrolled patients also makes them more representative. The operational challenges of large-scale clinical trials have led to more common instances of early-stage clinical success followed by late-stage failure. Roche's failure may also be attributed to this aspect.

So, has Roche's Phase III clinical trial really failed completely? In their press release, Roche mentioned that they observed numerical differences in the two primary endpoints. Additionally, the OS data is not yet mature and has not been disclosed.

"OS is the ultimate criterion to determine whether this drug works or not. If there is indeed a statistically significant difference in OS, then it can work as well."

Although the results so far have been unsatisfactory, the possibility left by the OS endpoint keeps Roche's "TIGIT Lung Cancer Dream" barely alive.

So far, almost all the clinical research results we have seen about TIGIT have come from Roche. Between hope and disappointment, time and again, Tiragolumab, as an "exception," along with the TIGIT track, has taken a thrilling roller coaster ride.

Labeling the TIGIT target as "viable" or "non-viable" based solely on the performance of Tiragolumab alone would inevitably appear biased. However, the aforementioned senior industry insider believes that Tiragolumab's setbacks imply a broader, more universal crisis.

In the conversation, he expressed concerns about TIGIT. Currently, there are already too many approved PD-(L)1 products globally, leading to stricter regulatory scrutiny for new products in various countries. Any new target or combination therapy must demonstrate efficacy compared to existing PD-1 products. However, "PD-1 is like the big brother among immune checkpoint inhibitors; discovering a new target as effective as PD-1 is very difficult, and other targets surpassing it is also challenging."

If the combination with PD-(L)1 cannot compete with PD-1, other research and development directions for TIGIT are likely to be even more challenging.

The industry insider who participated in the R&D of the TIGIT target mentioned above stated that the Phase II clinical data disclosed by Roche had already shown warning signs.

In the Phase II CITYSCAPE clinical trial, the objective response rate (ORR) of patients treated with Tiragolumab + Tecentriq combination therapy significantly improved to 31.3%, compared with 16.2% in the group receiving Tecentriq alone. While this data appears positive, it has also raised some doubts: "My first thought upon seeing the data was that Tecentriq's performance seemed a bit weak. In the earlier IMpower110 study, the ORR for Tecentriq monotherapy was around 40%. So, is this 16% just an anomaly? Therefore, I wasn't very optimistic at the time."

This data reminded him of Merck's PD-L1/TGF-β (M7824) bispecific antibody. Once, it was also a "chosen one" placed on a pedestal, but ultimately ended in failure after four clinical setbacks.

At the 2018 ASCO conference, Merck previously announced a set of positive clinical data for M7824. In 40 patients with advanced non-small cell lung cancer using the 1200mg dose group, the ORR (Objective Response Rate) for PD-L1 positive patients reached 40.7%, while the ORR for patients with high PD-L1 expression was as high as 71.4%.

Behind the impressive data lies the stringent enrollment criteria. Not only did Merck rigorously screen patients with varying levels of PD-L1 expression, but they also selected non-small cell lung cancer, a type known for relatively outstanding responses to PD-(L)1 treatments. In the eyes of some, Merck's data may also appear to have an element of chance; the notably high ORR could be the result of coincidentally selecting suitable enrolled patients.

PD-(L)1+TIGIT and PD-L1/TGF-β share some similarities, which inevitably raises concerns about the future direction of TIGIT.

This year, Roche will also release clinical data on the Tecentriq + Tiragolumab combination for the treatment of other indications such as esophageal cancer. The clinical data of Merck's Vibostolimab, GSK/iTeos' EOS-448, and Novartis/BeiGene's Ociperlimab are also highly anticipated. From the industry perspective, it is becoming increasingly challenging for many pharmaceutical companies to achieve breakthroughs with TIGIT, but there are still many possibilities.

As for Roche's Tecentriq+Tiragolumab combination, the current setback cannot fully determine its ineffectiveness in lung cancer. In subsequent clinical studies, Roche will continue to update the OS data of patients. As we mentioned earlier, the ultimate determinant lies in the yet-to-be-completed OS.

In the history of PD-(L)1, there have been precedents where PFS failed but OS was effective.Merck's Keytruda only demonstrated improvement in OS, but not in PFS and ORR, when treating PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma patients. However, these clinical research results were sufficient to support the approval of Keytruda for the HNSCC indication.

In the current era where OS is the gold standard, if Roche's OS data is statistically significant, the future of TIGIT remains promising.

Even if Tiragolumab ultimately fails to succeed, it is, after all, just one of dozens of companies that have entered the TIGIT drug development field. There are still more products similar to or differentiated from Tiragolumab that may achieve success in the future.

In terms of drug design mechanisms, the differentiation of TIGIT monoclonal antibodies is reflected in Fc functionality. Some antibodies, represented by Tiragolumab, have chosen to retain the Fc function of TIGIT monoclonal antibodies; whereas another group, represented by Gilead/Arcus Biosciences' Domvanalimab, has taken a different approach by removing the Fc functionality of the antibody to block immunosuppression and enhance immune activity. Additionally, some other antibody products have opted to enhance the Fc functionality of the antibody. Whether the presence or absence of the antibody’s Fc function will impact the clinical efficacy of anti-TIGIT antibodies remains to be seen, leaving more opportunities for the future development of TIGIT.

Tiragolumab is only the forerunner in the development of TIGIT, and the road ahead for TIGIT is still long. However, we should recognize that the research and development of an innovative drug in the pharmaceutical field is extremely challenging. In this industry where "failure is the main theme," learning from mistakes and moving forward, and finding ways to benefit patients clinically, are even more crucial themes.