The Ongoing Challenges Facing TIGIT Inhibitors in Lung Cancer: Part I

Please share your name, title, and a brief overview of your professional history.

Mark A. Socinski, MD: My name is Mark Socinski, and I’m the Executive Medical Director of the AdventHealth Cancer Institute in Orlando, Florida. I am a thoracic medical oncologist, and my previous positions included leading thoracic oncology programs at the University of Pittsburgh and the University of North Carolina.

I’ve been in my current position for 10 years, and I still maintain my practice in thoracic oncology and remain involved in ongoing clinical trials in this space.

Please share a brief overview of this study. What were your key findings?

Dr Socinski: SKYSCRAPER-06 was a phase 3 randomized clinical trial in the first-line treatment of metastatic non-small cell lung cancer (NSCLC). It was a multicenter, global study.

The question asked was based on the established standard of care: a platinum-based doublet plus immunotherapy. The control arm for this trial, which was restricted to advanced nonsquamous NSCLC, was what we refer to as the KEYNOTE-189 regimen: chemotherapy with carboplatin and pemetrexed plus pembrolizumab. That’s an established standard and probably the most commonly used platform we see, certainly in the United States.

The investigational arm of SKYSCRAPER-06 used the same chemotherapy backbone but substituted the programmed death ligand 1 (PD-L1) inhibitor atezolizumab for pembrolizumab, with the addition of tiragolumab. Tiragolumab is an anti–T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) compound.

The primary endpoints were investigator-assessed progression-free survival and overall survival. We were also interested in the safety and tolerability of the regimen. There were approximately 540 patients in the full analysis set, with about 270 patients in each arm. The baseline demographics were similar, as you would expect in a randomized trial.

As I mentioned, one primary endpoint was investigator-assessed progression-free survival, which was not statistically different between the 2 arms. In the tiragolumab arm, progression-free survival was 8.3 months, and in the control arm, which again was pembrolizumab plus chemotherapy, it was 9.9 months. The P value was .99, indicating essentially no difference.

That was also true for the survival outcomes. Median overall survival in the tiragolumab arm was 18.9 months, compared with 23.1 months in the control arm. The hazard ratio was 1.33, and the P value was .98.

This was a negative study for superiority. Noninferiority was also tested, and it did not meet its noninferiority endpoint either. The final statistical conclusion from this trial was that the investigational regimen was neither superior nor noninferior.

When considering adverse events, I think the one thing we must remember is that we’re comparing a 3-drug regimen with a 4-drug regimen. As we always see, the more drugs you use, the more toxicity you would expect.

I think we did see slightly more toxicity with the 4-drug regimen, as expected. But was the toxicity out of order, if you will, for a 4-drug regimen? I don’t think so. There was a slightly higher rate of grade 5 adverse events on the investigational arm with tiragolumab, but if you look at treatment-related grade 5 events, they were roughly equivalent between the 2 arms.

At the end of the day, neither of the primary endpoints was reached, and the study has subsequently been terminated.

The SKYSCRAPER-06 trial was built on strong biologic rationale and encouraging early-phase TIGIT data, yet the phase 3 results were negative. From your perspective, what do these findings reveal about the challenges of translating early immunotherapy signals into meaningful survival benefits in advanced NSCLC?

Dr Socinski: I’m going to give you an answer both as a lung cancer expert and from an immunology standpoint.

If you look at the history of lung cancer—and my history goes back 3 decades—we have repeatedly seen phase 2 trials that look “promising” and are considered positive trials. Of course, the struggle we always have with phase 2 trials, even randomized phase 2 trials, is whether the signal of positivity is strong enough to drive a survival advantage in the phase 3 setting.

I can tell you that there’s a long record of phase 2 trials perceived as positive that failed in phase 3. This is the current legacy of NSCLC: getting a hint that a treatment might work but then failing the true test of efficacy in phase 3. I often say that the “cancer highway” is littered with phase 2 trials that never panned out in phase 3 studies.

The second perspective involves understanding the immune system. This comes with the caveat that I’m not a trained immunologist, and there are many intricacies of the immune system that are beyond my scope of expertise.

I think we’ve clearly established that manipulation of the immune system is possible. The outcomes we’re seeing in populations treated with either immunotherapy alone or chemoimmunotherapy are unlike anything we saw with standard chemotherapy.

I can tell you that in my personal practice, years ago, we would say that metastatic lung cancer was treatable but not curable. I think we are now curing some patients with metastatic lung cancer.

In my clinic, I have many patients who received immunotherapy alone or chemoimmunotherapy and are now beyond 5 years, thriving, and still in remission. Are they cured? I don’t know—stay tuned. But achieving a 5-year survival with no evidence of disease progression sounds like a cure to me.

Now, having said that, we’ve had such a major step up in the standard of care with the addition of programmed cell death protein 1 (PD-1) and PD-L1 inhibitors—somewhat less so with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, although we’re still waiting for some trials to mature that may change that somewhat.

The question now is: what’s next?

The tumor microenvironment is very complex at the level of the tumor, and predicting how to manipulate that beyond the PD-1/PD-L1 strategy is really difficult.

One of the other difficulties is that I think some patients would likely benefit from new immune-directed therapies such as anti-TIGIT agents. However, the issue is that it’s not a one-size-fits-all approach.

We don’t have validated predictive biomarkers that identify which patients would benefit from anti-TIGIT therapy, and that’s really the big challenge here.

We know TIGIT is important in disrupting costimulatory signaling within the tumor microenvironment. The balance between inhibitory and activating signals at that level may be part of the reason we haven’t seen success with anti-TIGIT strategies.

Certainly, we know that PD-1 and PD-L1 inhibition works in patients with an inflamed tumor microenvironment, as detected by high PD-L1 expression. If you have very high PD-L1 expression—which is an immune biomarker we understand—single-agent PD-1 or PD-L1 inhibitors clearly have a role.

However, we haven’t really been able to identify the biomarkers or microenvironmental factors that would predict benefit from anti-TIGIT strategies.
That’s where we struggle. It’s not easy. We went through the same phase with anti–vascular endothelial growth factor (VEGF) inhibitors. We really don’t have a biomarker for drugs such as bevacizumab or ramucirumab. Part of the issue is that these drugs target genetically stable and normal aspects of being human.

The same is true with the immune system.

That’s where I find the struggle here. Although there was initial enthusiasm in the TIGIT field, that enthusiasm has been dulled substantially, partly because of the SKYSCRAPER-06 trial.