My talk is actually on a very provocative and very important and interesting theme, it’s on how we are cracking the code in small cell lung cancer with bispecific immunotherapy.

What makes small cell lung cancer particularly challenging, and how could bispecific immunotherapy address these challenges?

What I will also address in my talk is that small cell lung cancer is the most difficult site in oncology. We have a stagnation in innovation over the last 30 years. Why? Because this is a tumour that although it should be highly immunogenic, unfortunately it’s not. It has several mechanisms that evade immune cell variants; in a way it has very specific mechanisms that can camouflage from the immune system.

So bispecific immunotherapy is actually a novel strategy that is not actually trying to solve the code but is actually bypassing the whole encryption. This is the very interesting point about this new strategy – it actually goes beyond the traditional ways of solving immune evasion mechanisms.

How do bispecific antibodies work differently from traditional immunotherapy in SCLC?

One of the problems with immune evasion for small cell lung cancer is that actually T-cells cannot enter the tumour, cannot access the tumour. Also, even when they access it, it’s like quicksand. So when they get there they get very dysfunctional. So what we do with bispecific antibodies is that we don’t rely on T-cells infiltrating the tumour, we just attract them by creating a bridge between the target, which is DLL3, a target that is very highly expressed in small cell lung cancer, more than 80% of small cell lung cancers express DLL3, and also on CD3 on T-cells.

So what they do, the bispecific molecules is that they create this bridge and they actually bring the T-cells to the tumour site, bypassing the MAC downregulation, the non-recognition, and also the dysfunction of T-cells.

What clinical evidence do we have so far on efficacy and safety in this space?

We have a very important molecule which is first in class – it’s tarlatamab, as you know. It’s a DLL3 T-cell engager and we have a whole clinical programme, starting with very early data on the study DeLLphi-301 which was actually the study that gave the approval to this agent in second line. But now we also have data presented last year from the DeLLphi-304, which is a phase III randomised study, versus the standard of care chemotherapy in second line. From these studies we have shown that there is a significant, a very clinically meaningful benefit in overall survival. So while with chemotherapy the median overall survival in second line is approximately 6-9 months, now with tarlatamab we can push that. We pushed that up to 13 or more, 13-14 months. This is talking about patients in second line, so it is a very, very meaningful benefit in survival – almost 5 months benefit to what we had so far in second line.

However, this doesn’t come without the expense of toxicity. We have learned that these molecules have very different toxicities, toxicities that we have to be aware from the beginning. Many colleagues are still frightened of utilising these molecules on an outpatient basis because they need to be monitored, the patients need to be monitored and hospitalised probably for the first 24 hours. But in most places with experience we can now move these treatments on an outpatient basis.

Where do you see bispecific immunotherapy fitting into the future treatment landscape of SCLC?

At the moment tarlatamab has changed the second-line setting but we are moving very fast to the first-line setting. Because small cell lung cancer also has other layers of complexity and one is moving from under therapeutic pressure, moving to different subtypes. This is one thing that we also need to overcome and this we can overcome by combining these molecules with what we already have, so with checkpoint inhibitors, or by using newer, next generation molecules, the trispecific antibodies, which actually come to help us more to get better to the target.

So what I see in the future is combinations of these molecules with what we already have – chemotherapy and immunotherapy – in the first-line setting.

Is there anything else you would like to add?

The most important thing is that nowadays we can start thinking of small cell lung cancer as one more cancer that we should move towards precision. This is something that was unthought a few years ago but with the recent discoveries and innovations and the new molecules, I think that we are looking towards a future of precision oncology also in small cell lung cancer.