Sally Lau, MD, Perlmutter Cancer Center, New York, New York, discusses results from the phase 1b DeLLphi-303 study. Results demonstrated that tarlatamab, a t-cell engager, plus a PD-L1 inhibitor exhibited efficacy and safety as first-line maintenance therapy for patients with extensive-stage small cell lung cancer (SCLC). 

Dr Lau presented these results at the 2024 World Conference on Lung Cancer (WCLC) in San Diego, California. 

Transcript: 

My name is Sally Lau and I'm an assistant professor and thoracic medical oncologist at the NYU Perlmutter Cancer Center. The DeLLphi-303 study is a phase 1b study looking at the combination of tarlatamab with a PD-L1 inhibitor as maintenance therapy in first-line extensive-stage small cell lung cancer. 

The rationale for doing this study is that when we looked at tarlatamab, which is a t-cell engager, in the relapsed/refractory setting we saw very durable objective responses and whenever we see a therapy that works so well in the second-line setting we really want to look at moving that therapy up so that patients can get it right from the get go. Based on some preliminary studies in the lab we saw that when we combine it with the PD-L1 inhibitor we see better responses so in this study, the DeLLphi-303 study, we combined both tarlatamab and a PD-L1 inhibitor together and we moved it up earlier in a patient's treatment setting so that we can seek the maximal benefit. 

The study design is really a phase 1b study, patients who received standard-of-care platinum-doublet chemotherapy and a PD-L1 inhibitor were then allocated to tarlatamab with either atezolizumab or durvalumab, both of which are standards of care in small cell lung cancer, and this study evaluated the combination of tarlatamab together with a PD-L1 inhibitor and we continued that combination until disease progression or until unacceptable toxicity. 

Two very important results we want to look at: one is the safety of that combination and the other is efficacy, and as this is a phase 1 study, I can go into the safety first. The safety was very tolerable and we didn't see anything that was unexpected. We do see the most common side effects being CRS or cytokine release syndrome, the second being dysgeusia, which is a unique side effect that we now know as likely to be a class effect of these DLL3-targeting drugs because DLL3 are actually expressed on taste buds. Besides these two we saw side effects of fever that is not related to CRS and fatigue as the most common side effects. Overall the safety profile is very well tolerated. We also know with these t-cell engagers that there are unique side effects like CRS or ICANs [Immune effector cell-associated neurotoxicity syndromes] which are seen really with the first two doses in the study, and it wasn't anything different compared to tarlatamab as a single-agent. What was also important is that when it was combined with the PD-L1 inhibitor we didn't see any increase in the side effects and the overall incidence in the toxicity profile is similar to what we see with tarlatamab alone in the second-line studies. 

What was much more exciting is also the durability and the efficacy of this combination. We see some unprecedented survival results. In the first-line setting, we are seeing that on average, the median progression-free survival was 5.6 months, and also remember that this 5.6 months is measured from the start of maintenance therapy and the median time to starting maintenance therapy was 3.6 months, so these patients with extensive-stage small cell lung cancer are really not progressing until 8 months into therapy and that is something that we haven't seen before with chemotherapy and immunotherapy. 

We also see some very encouraging results with the tail-end of the curve and these are patients that really look like by the time they get to 9 months of maintenance therapies, they're not really progressing and that curve flattens out, and that flattening out of the curve at 9 months is 39% and that is something that is very, very encouraging to see in small cell lung cancer. 

The overall survival data is not mature, but we can see from the trend that again, the results are very promising. At 9 months or 12 months from the time of starting first-line therapy we're seeing an overall survival of 89% and that is something that we haven't seen with any other therapies in small cell lung cancer. I think the impact is really huge with these results. 

Small cell lung cancer is a disease that really hasn't had any breakthroughs for the last 30 years and seeing these agents make a difference really brings hope to patients with this devastating disease. It's also very exciting because tarlatamab is a t-cell engager, essentially an antibody that is bispecific recognizing DLL3 and bringing in the t-cells right up to the cancer so that it can activate for killing. It's the first-in-class to be approved in solid tumors and this is definitely very exciting and also really highlights the fact that when we understand why small cell lung cancers do not respond to PD-L1 inhibitors and we design a drug that can bypass those mechanisms of resistance, we can actually leverage the immune system for these very exciting results.

This is a phase 1b study and it really does provide the rationale for investigating this combination in a phase 3 setting so that patients can get access to this. 

The next step really is we definitely want to see data maturity and we want to see what, or we want to get a sense of what the median overall survival is and how much that is improved compared to the standard, which is immunotherapy and chemotherapy together. This provides us with a rationale to investigate this combination and next to come is really the DeLLphi-305 study, which is a phase 3 study randomizing patients to tarlatamab plus durvalumab versus durvalumab alone, and that will give us the gold standard in comparison to the current standard of care. To kind of further move the therapy up, there's also a phase 3 study called the DeLLphi-306 study looking at the addition of tarlatamab in limited-stage disease, so patients that we think normally would be treated with chemotherapy and radiation, to add tarlatamab on at the end as maintenance therapy to improve the overall survival of these patients. 

I think the most exciting thing about these studies is the tail-end of the curve and the potential for really long-term durable responses. I think it really does highlight the fact that if we can leverage the immune system well, it can give us exceptional responses. Besides moving tarlatamab up in therapies, I think the other exciting area that we can look at is really combining the [bispecific T-cell engagers] BITEs with other novel therapies to leverage the immune system to give us these durable responses and these long-term responses so that they're not just limited to 30% of the patient population, but so that more and more patients can benefit from these therapies. I think it really underscores the importance of understanding the science and the biology of these tumor types.

Source: 

Lau S, Ahn MJ, Moskovitz M, et al. Tarlatamab with a PD-L1 inhibitor as first-line maintenance after chemo-immunotherapy for ES-SCLC: DeLLphi-303 phase 1b study. Presented at the 2024 World Conference on Lung Cancer. September 7-10, 2024. Abstract OA10.04