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

How should clinicians interpret these results when considering the future role of anti–T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) inhibitors in lung cancer?

Mark A. Socinski, MD: After some initial enthusiasm, the first trial, if I remember correctly, was CITYSCAPE. However, CITYSCAPE was conducted in the absence of chemotherapy, whereas SKYSCRAPER-06 used chemotherapy.

Could chemotherapy negatively affect some immune strategies? That’s a hypothesis that’s currently being explored. Is there a role for TIGIT strategies integrated into regimens without a chemotherapy backbone? Some of those results haven’t been positive either.

It appears that a one-size-fits-all TIGIT approach for all patients is probably not the correct strategy. We lack a predictive biomarker for anti-TIGIT strategies, and we don’t know how to prospectively select patients or identify a population that would benefit.

Another lingering question is: what should be the partner for an anti-TIGIT strategy? Is it another immunotherapy drug? Is it chemotherapy? Chemotherapy doesn’t seem to be the answer at this point.

Programmed death ligand 1 (PD-L1) inhibitors work very well with chemotherapy, but that doesn’t seem to be the case here. There are various hypotheses about why TIGIT may not synergize well with chemotherapy. Certainly, SKYSCRAPER-06 suggests that TIGIT doesn’t seem to work well with chemotherapy, and it doesn’t really answer or resolve that question.

Another variable in SKYSCRAPER-06 is the use of a programmed cell death protein 1 (PD-1) inhibitor—pembrolizumab—on the control arm versus atezolizumab, a PD-L1 inhibitor, in combination with tiragolumab on the investigational arm.

Is there an issue with atezolizumab in that setting? We haven’t seen head-to-head comparisons of these PD-1 and PD-L1 inhibitors, and I don’t think we ever will. However, that remains an outstanding question raised by this trial as well.

Where do you see the field of immunotherapy innovation in non-small cell lung cancer (NSCLC) heading next? Are there emerging pathways, biomarkers, or combination approaches that you believe hold promise?

Dr Socinski: There are several emerging immune-related strategies—not only in lung cancer, but across many disease settings. There are also other targets, such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3). Vaccine strategies are also being explored. Tumor-infiltrating lymphocyte (TIL) strategies are under investigation as well. Will there eventually be a role for chimeric antigen receptor (CAR) T-cell approaches in this setting? I don’t know yet. They remain highly investigational in thoracic oncology.

I think all these approaches deserve study because the initial wave of PD-1 and PD-L1 therapies clearly demonstrated that manipulation of the immune system can work in lung cancer.

These approaches have shown efficacy in both non-small cell (NSC) and small cell lung cancer (SCLC). In fact, we also have an indication in mesothelioma. Across thoracic malignancies, immune manipulation appears to be an effective strategy, and there are additional targets that need to be studied to determine how we can maximize that effect.

However, if you ask me what’s ultimately going to be the winner, I go back to my earlier comment: the lung cancer highway is littered with early studies that never panned out in phase 3 settings. We’ll just have to wait and see. Certainly, there is a plethora of ideas out there, all of which I think are worth studying and are being evaluated in many ways. However, we’ll need more mature data.

I also think it’s always helpful for these early studies to include a control arm, if possible, because sometimes these therapies look very promising early on because they truly are effective—and sometimes they appear promising because of patient selection. At least in a randomized trial, you can neutralize the issue of patient selection.

I also would like to make a plug for clinical trials. We have many ongoing clinical trials, but only a very small percentage of patients with lung cancer enroll in clinical trials. 

I’ve always said that a patient going on a clinical trial starts with their oncologist. The oncologist must recommend it and support it. Given the number of studies available, if a clinical trial is an option, oncologists should support and recommend the opportunity for their patients. That’s how we continue to define new therapies and determine which therapies are not going to work.

Many good ideas don’t pan out, but there are also many good ideas that do. Certainly, the treatment options we have for patients today compared with 30 years ago are exponentially better, and we are seeing improved patient outcomes.