Emerging Treatments in SCLC: Bispecific Antibodies

Hossein Borghaei, DO, MS: I’d like to move on to our third and final section. We’re going to talk about some emerging approaches for the management of small cell lung cancer. Wade, I’m going to start with you. There have been a couple of interesting presentations regarding AMG 757 and then a second agent, BI 764532. If you don’t mind, briefly go over the data and try to put it into some context for us, please.

Wade Iams, MD: This preceding discussion was a perfect segue for novel immunotherapy approaches and DLL3-targeted agents. I’ll discuss 2 different drugs in development. They’re both bispecific T-cell engagers. Within the broad field of oncology, the best analogy for drugs to these DLL3 agents is blinatumomab, a bispecific CD3/CD19 antibody, for patients with acute leukemia. In the context of small cell lung cancer, the data I’ll review have to do with novel drugs that are bispecific antibodies to DLL3—which is expressed in a majority of small cell lung cancer tumor cells, it doesn’t directly coincide to any of the subtyping we’ve discussed, it’s fairly independent of subtype—and CD3.

The goal of both of these drugs is to bring the host T cells to those small cell tumor cells. The first abstract that I’ll talk about is Amgen [Inc]’s AMG 757. This was a first-in-human dose-escalation study. Sixty-four patients were treated with the AMG 757 compound. It’s an IV [intravenous] infusion every 2 weeks. First, there are a couple of disclaimers before I tell you about the response and toxicity data. In relapsed small cell, we need to think about how much treatment these patients have received. The median number of lines of therapy was 2, so we’re generally talking about the third line of therapy or later. This is a difficult patient population with small cell lung cancer. These patients were in a dose-escalation cohort. That’s the caveat with the response data.

The response rate for partial responses was 13%. The disease control rate was about 43%. But as all of the panelists have touched on this evening, durable response is what we’re hoping for with these immunotherapy drugs. And among patients who responded, 71% had over 6 months of response. In a majority of patients who responded, it was very durable. That’s the high point of the DLL3 data, in my opinion.

Toxicity-wise, we’re always monitoring for cytokine release syndrome, which is essentially an acute inflammatory syndrome, in patients receiving these drugs, and 42% of them had any degree of cytokine release syndrome. In about a quarter of them, it was grade 3 or greater. We’re talking a need for observation and probably hospitalization in those patients. There was 1 participant who had a grade 5 pneumonitis event. There’s notable toxicity with this approach, but we’re going for that durability of benefit.

Hossein Borghaei, DO, MS: Were there any data regarding lines of therapy associated with toxicity in this patient population?

Wade Iams, MD: Not that I’m aware of, but it’s a key question. In thoracic oncology in particular, when we’re looking at these phase 1 trial data, I’m always asking, “Is that a patient who had pneumonitis from a previous JAK1 inhibitor?” We’ve all seen that confound later lines of therapy, and it can be quite delayed. It’s a key question.

The second compound, also a bispecific T-cell engager, is from Boehringer Ingelheim [BI]. This abstract is just a plan for a first-in-human trial of that drug. Here are a couple key points on this upcoming trial. They’re looking to enroll 110 patients. A couple of interesting caveats for the BI trial: They are selecting for DLL3 tumor expression, and they’re including not just small cell lung cancer, but small cell of any type. In the broad oncology field, that’ll be well received, as we know there are different histologies that can transform to small cell. That’ll be very interesting to see.

Hossein Borghaei, DO, MS: Thank you so much for providing that update for us. Let’s go through the updates, and then we’ll have another discussion. Stephen, TIGIT is getting a lot of attention in both non–small cell and small cell. There’s an abstract involving small cell. I’m wondering if you can comment about that.

Stephen Liu, MD: Sure. There aren’t a whole lot of data to review here. TIGIT stands for T-cell immunoreceptor with Ig [immunoglobulin] and ITIM domains. It inhibits T cells and NK [natural killer] cells, another checkpoint. Tiragolumab is an anti-TIGIT IgG1 monoclonal, where we have a little data. The data are mostly from non–small cell lung cancer. Our colleague Delvys Rodriguez-Abreu, [MD,] presented the CITYSCAPE data. That’s a randomized phase 2 trial in non–small cell lung cancer. We saw that when you added an anti-TIGIT like tiragolumab to an anti–PD-L1 like atezolizumab, it significantly improved the response rate in PD-L1–high from 24% to 66%, improved PFS [progression-free survival], and the hazard ratio was a staggering 0.30, awarding that drug FDA breakthrough therapy designation.

We have multiple anti-TIGIT molecules in development now, and we’re looking at them in small cell lung cancer. SKYSCRAPER-02 is a randomized phase 3 trial. For full disclosure, I am on the steering committee of that trial. That’s looking at the IMpower133 regimen of carboplatin, etoposide, and atezolizumab with or without tiragolumab, or placebo. It’s a study of almost 500 patients and dual primary end points, PFS and OS [overall survival]. It’s no longer recruiting patients, so we’re eagerly awaiting the results from that trial.

Hossein Borghaei, DO, MS: That’s great.

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