The weather vane Roche "broken down", and the TIGIT target of the rising star hangs?

In the past period of time, the TIGIT target has been highly anticipated and seen as the next PD-1
.

Most of the valuation of BeiGene, the first domestic innovative drug, is supported by a TIGIT monoclonal antibody that is leading the world

"In the past eight years, I don't know that PD-1 is outdated in the industry; TIGIT is a very popular target recently, and it must be remembered in the future
.

" In July 2020, Wang Lai, senior vice president of BeiGene, said this

Now it seems that the TIGIT target is indeed well-known; but whether it can become the next PD-1, there is still a question mark
.

On March 30, Genentech, a subsidiary of Roche Group, said that TIGIT monoclonal antibody Tiragolumab in combination with PD-L1 failed as a first-line therapy for the treatment of extensive-stage small cell lung cancer
.

Although small cell lung cancer is a black hole in research and development, the prospect of TIGIT targets depends mainly on whether it can succeed in the field of non-small cell cancer
.

But Tiragolumab, as the pioneer of TIGIT monoclonal antibody, its failure will still make the market think about it
.

At the very least, it may change the market's understanding and expectations of TIGIT's future

So, can the TIGIT target finally be successful?

/ 01 / PD-L1+TIGIT combination therapy fails for the first time

/ 01 / PD-L1+TIGIT combination therapy fails for the first time

After PD-(L)1, everyone is looking forward to the next immune checkpoint that can become a "blockbuster"
.

And TIGIT is considered to be one of the most promising and potential targets

TIGIT is a T cell immunoglobulin and ITIM domain protein, belonging to the PVR (poliovirus receptor)-like protein family.
Checkpoint proteins
.

The development of the TIGIT target did not go well at first
.

On June 23, 2020, Roche announced the Phase 1a clinical trial of the TIGIT antibody Tiragolumab as a monotherapy in non-small cell lung cancer
.

The TIGIT antibody tiragolumab monotherapy had an overall response rate of 0 in 24 patients
.

This also means that TIGIT monoclonal antibody is basically ineffective for patients with non-small cell lung cancer

However, the target of a finished drug can be met but not sought after, and one failure cannot prove anything.
Roche believes that TIGIT monoclonal antibody may be able to "rescue" it again
.

After all, the third immune checkpoint LAG-3, which was just approved not long ago, is also ineffective as a single drug, but it has shown good results in combination with PD-1
.

To this end, Roche has deployed a number of combination therapies of TIGIT and PD-1, hoping that Tiragolumab can come back to life
.

In December 2021, the combination therapy demonstrated strong effects in a phase 2 clinical trial for patients with high PD-L1 expression (TPS ≥ 50%), with data showing:

The median OS of PD-L1 monotherapy in the control group was 12.
8 months, not yet reached in the PD-L1+TIGIT group, and the risk of death was reduced by 71%
.

That is to say, as of the release of the data, more than half of patients using the combination therapy are still alive

In terms of objective response rate, PD-L1 monotherapy vs combination therapy was 24.
1% vs 69%; mPFS (median progression-free survival) was 4.
1 months vs 16.
6 months, respectively
.

For non-small cell lung cancer, the combination of PD-L1 and TIGIT has a considerable effect
.

But just when everything was on the right track, the plot changed again

Today, Roche announced the results of a Phase III clinical trial of PD-L1+TIGIT+ chemotherapy as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC).
Compared with chemotherapy, the two primary endpoints, PFS and OS, were not met
.

That is to say, the combination of the two can neither improve the overall survival of patients nor control tumor progression
.

There is no doubt that this poured cold water on the enthusiasm of the TIGIT target

/ 02 / TIGIT target prospect is surging

/ 02 / TIGIT target prospect is surging

So, will the TIGIT target be sentenced to "death penalty" for this failure? It is too early to draw conclusions
.

Because in terms of indications, the population of patients with extensive-stage small cell lung cancer is not large
.

Lung cancer is subdivided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which NSCLC is the most common, accounting for about 85% of all lung cancer cases in the United States and Europe, and has the highest mortality rate
.

Small cell lung cancer only accounts for 10-15%, and more than 2/3 of the patients are newly diagnosed extensive stage (ES-SCLC)
.
Therefore, for PD-L1+TIGIT, non-small cell carcinoma is still the main battlefield, and it is not a complete failure if the main battlefield is not lost
.

Furthermore, ES-SCLC is a difficult-to-treat cancer type
.
Since the 1980s, there has been no breakthrough in the treatment of SCLC, and the current treatment of SCLC is still based on chemotherapy, radiotherapy and palliative care
.

Roche's PD-L1 drug Tecentriq was the first cancer immunotherapy to show a survival benefit in a Phase III clinical trial for ES-SCLC and the first approved treatment in 20 years
.

Perhaps it is this factor that makes Roche and Genentech want to challenge the difficult ES-SCLC
.
However, ES-SCLC cancer is really difficult to overcome, so TIGIT mAb cannot be completely rejected because of this failure
.

For the TIGIT/PD-L1 combination therapy, the highlight is still in the field of non-small cell lung cancer
.
This is also the decisive battle to decide the fate of TIGIT mAb
.

Roche also said that it will continue to evaluate the effect of Tiragolumab combination therapy in phase III clinical trials of non-small cell lung cancer and other cancers
.

According to public information, a phase III clinical trial SKYSCRAPER-01 for patients with high PD-L1 expression is expected to complete the clinical trial in August 2022
.
At that time, the prospect of the TIGIT target may be answered in the affirmative
.

There is still hope for the TIGIT target, but it is undeniable that Roche's failure will also bring worries to the market
.
After all, the mechanism of action of TIGIT targets is complex
.

The combination of single-drug ineffectiveness and PD-1 drugs shows a certain early efficacy, but it is not without stamina in the third clinical phase, such as IDO inhibitors
.

The development of innovative drugs is always full of uncertainties
.
No one can be completely indifferent to a clinical failure
.

This may also affect the decision-making of domestic players
.
There are many domestic TIGIT players, and BeiGene, which is the most advanced, is even in the same echelon as Roche and Merck
.

When the prospects for drugs are good, this kind of advancement is exciting; but if expectations deteriorate, and if TIGIT fails, the pharmaceutical companies standing at the forefront will inevitably be hit harder
.

In the face of Roche's failure, can domestic players' confidence in TIGIT monoclonal antibody remain as firm as ever?

/ 03 / Combination therapy is not necessarily a lifesaver

/ 03 / Combination therapy is not necessarily a lifesaver

In recent years, the development of combination therapy is in full swing
.

It is not surprising that the emergence of PD-1/PD-L1 antibodies has successfully brought cancer treatment into a whole new field
.
PD-1 drugs can not only produce deep responses in some patients, but also have better safety than traditional chemotherapy drugs
.

But this seemingly perfect drug has a fatal flaw
.
PD-L/PD-L1 has always had the problem of low response rate, and the single-drug effective rate is only 20%-30%
.

How to enable more patients to respond to PD-1 has become an urgent clinical need
.
At the same time, this is also a breakthrough for many latecomers of PD-1 to break through the blockade of K and O drugs and to divide up the PD-1 market
.

And it seems that combination therapy is currently the best solution to this problem
.
It is also because of this that Liao combined therapy around PD-1 has been carried out in an endless stream
.

According to a report published in "Nature Reviews Drug Discovery", there are currently as many as 4062 clinical trials worldwide evaluating the combination of PD1/PDL1 mAbs with other immunotherapies, targeted therapies, chemotherapy and radiation therapy
.

Although many "PD-1+X" packages have been tried, only a few of them can really show the effect
.
Up to now, there are only two approved combination therapies of PD-1 and other targets, one is PD-1+CTLA-4, and the other is PD-1+LAG-3
.

Beyond that, more combination therapies have either failed or are struggling to prove their effectiveness
.

From the failure of the combination of IDO inhibitors and PD-1 to the current failure of PD-L1+TIGIT for small cell lung cancer, it shows that in the field of biopharmaceuticals, let alone the results of 1+1>2, even the results obtained The result of 1+1=2 is not easy
.

Regarding the popularity of combination therapy, the discoverer of PD-L1, Professor Lie Ping, is even more cautious.
In his opinion, the current combination therapy is more random or even blind combination
.

And a study in Clinical Cancer Research said that after evaluating 13 immunotherapy drug combinations, it found that the combination therapy benefited from the individual effects of each drug, rather than synergy
.

Of course, this does not mean that there is a problem with exploring combination therapy.
After all, the essence of science is exploration, and it is also true for biopharmaceuticals
.
It’s just that for the exploration of combination therapy, we can’t give up the awe of science, and we should choose combination therapy with a more rigorous attitude
.