A Late-breaking session at the American Society of Clinical Oncology (ASCO) 2022 Annual meeting, which was held 3-7 June 2022, in Chicago, IL, featured the primary results of the SKYSCRAPER-02 (NCT04256421) trial in patients with untreated extensive stage small cell lung cancer (ES-SCLC), presented by Prof. Charles Rudin (Memorial Sloan Kettering Cancer Center, New York, NY). The primary results showed that adding tiragolumab to a backbone of atezolizumab with carboplatin and etoposide did not improve progression-free survival in this cohort.

Patients with untreated ES-SCLC were randomized patients to an arm with add-on triagolumab (n=243, 600 mg IV) or placebo (n=247, IV administration) in addition to standard of care backbone of atezolizumab with carboplatin and etoposide (1200 mg IV atezolizumab for 4 x 21-day cycles). With a median follow-up of 13.9 no additional benefit was seen for the tiragolumab arm in PFS or OS compared with the placebo arm (not significant). Safety results were promising; grade 3/4 adverse events occurred in 52.3% of the tirgolumab arm versus 55.7% of the placebo arm. Grade 5 TRAEs occurred in 0.4% in the investigational arm, and 2.0% in the placebo arm.

Physician’s Weekly spoke with Prof. Rudin:

“SKYSCRAPER-02 was a randomized phase 3 trial for patients with newly diagnosed extensive stage small cell lung cancer.  Building on a prior study, the IMpower133 trial, which defined the role of immunotherapy for small cell lung cancer, our prior standard was a chemotherapy doublet, and the IMpower133 study showed a survival benefit to the addition of a PDL-1 inhibitor atezolizumab to that backbone [2]. The SKYSCRAPER-02  trial attempted to further augment the immunotherapy by adding another immune checkpoint inhibitor, this one targeting a molecule called TIGIT.

So the trial was very simple: it was the 3 drug standard of care regimen with or without the addition of the fourth drug which is called tiragolumab, an anti-TIGIT antibody. It was a large international phase 3 trial. The bottom line was the tiragolumab molecule did not appear to add a benefit for patients with extensive-stage small cell lung cancer.

The progression-free overall showed no difference between the arms.”

What are the conclusions you can draw from this? Obviously adding the TIGIT did not help it. Is atezolizumab actually optimized at this point?

“It is not optimized. I think we need better strategies for these patients.

Still the large majority of patients with small cell lung cancer die of disease. I think atezolizumab is a step in the right direction and is an important proof of principle that this tumor is potentially responsive to immunotherapy, but based on the IMpower133 trial and the CASPIAN trial, which was very similar, adding durvalumab, my take from those trials is that only about 10 or 15% of patients with small cell lung cancer have tumors that are really responsive to immunotherapy. So clearly we need to do better. We need to define strategies to see if we can get the other 85, 90% of patients to respond to immunotherapy. Because when those responses occur, they can be transformative. They can be durable.

This trial told us that TIGIT is probably not the answer; that is, it’s probably not the relevant checkpoint that we need to activate for patients with small cell lung cancer. It takes it off the list, but I think it allows us to focus on other potential strategies to benefit a larger segment of the population.

I think the things we can conclude from the trial, it did very much confirm the results seen in the IMpower133 trial, that is, we saw exactly the same progression-free and overall survival as was previously seen in that trial. And that helps to sort of solidify and reinforce that result showing a benefit for immunotherapy. Furthermore, the tiragolumab molecule is very safe, that is, there wasn’t really any significant additional toxicity added in the investigational arm. That is important, not for the patients with small cell lung cancer, but for other diseases in which tiragolumab is being investigated where the safety signal will be of use.”

Now that we’re able to cross off TIGIT what are the next strategies to be tested?

“I think there are a lot of possible strategies. Certainly in the preclinical research space, there are many people interested in strategies to inflame the tumor using DNA damage response pathway inhibitors, things like PARP inhibitors and ATR inhibitors,

WEE-1 inhibitors and others, small cell lung cancer has defects in cell cycle progression that makes it susceptible to these types of inhibitors.

A number of preclinical studies suggest that inhibiting these pathways can lead to tumor inflammation, upregulation of pathways that inflame the tumor and may augment immune response.

We’re quite interested in epigenetic pathways that may also lead to better antigen presentation by tumors that may lead to a broader array of cancers responding to immunotherapy.

Those strategies are still, I would say, very much in the preclinical investigation phase, but I think we’ll be moving to the clinic in the next few years.”

Patient selection, really important for knowing which patients might respond, What’s the current strategy and where are we moving towards?

“One of the things we’re really interested in in small cell lung cancer is subtypes of disease and our group and others have defined subtypes based on what we call master transcriptional regulators ASCL1, NEUROD1, POU2F3 [3-5]. We think that these define subsets of disease that may be very different in terms of their immune context and in terms of their response to targeted therapies.

I think one way forward for small cell lung cancer generally is to define patients that have distinct therapeutic vulnerabilities and may respond very differently to targeted inhibitors based on which of these subtypes the tumor fits into. So we’re very interested in trying to use these sort of markers to define patient subsets that may be more responsive to particular targeted agents or immunotherapies as a way forward for the field.”