Emerging Agents and Future of Small Cell Lung Cancer

Stephen V. Liu, MD: Small cell lung cancer has such a high rate of attrition. The biggest impact will always be in the first-line setting. We’ll see empiric strategies that try to build on the chemoimmunotherapy approach validated by the IMpower133 and CASPIAN trials. The addition of thoracic radiation, alternate maintenance strategies, or incorporation of more immunomodulatory agents, like anti-TIGIT [T-cell immunoreceptor with immunoglobulin and ITIM domain] antibodies, will help build on those outcomes we see in extensive-stage small cell lung cancer. We’ll start to work on selective delivery of agents. We need to identify the unique subsets that exist within small cell lung cancer that can be treated differently. Empiric therapy is only going to take us so far. We desperately need predictive biomarkers that can guide therapy. There is a lot of enthusiasm for expression of transcriptional regulators as a guide. We still, however, need clinical data to validate this approach. Ultimately, we will need prospective data to see if this is an effective strategy going forward.

There are many active agents and combinations in development. Liposomal irinotecan was granted fast-track designation by the US FDA. In part 1, we saw a response rate of over 40%, which is exciting, but we need to wait for results from part 2, where patients are randomized to nal-IRI [nanoliposomal irinotecan] or topotecan. We need to reserve judgments for these agents until we see randomized data because we’ve seen responses before. A good example is amrubicin. In phase 2 studies, amrubicin showed high response rates, some over 50%, 60%. But in a randomized trial, those response rates didn’t translate to a survival benefit over standard topotecan. A similar example is the combination of lurbinectedin plus irinotecan. There was a high response rate, 62%, and 69% in chemotherapy-sensitive disease, but it’s not clear this is going to lead to any improvement in survival. In addition, that combination was fairly toxic, with 29% grade 3 diarrhea, 62% grade 3 neutropenia.

I am looking forward to seeing more data from AMG 757. This is a bispecific T-cell engager [BiTE] that targets DLL3. We know DLL3 is selectively expressed on small cell lung cancer and large cell neuroendocrine tumors. An antibody-drug conjugate, rovalpituzumab tesirine, was unfortunately too toxic, and not effective enough to demonstrate enough efficacy in DLL3-positive small cell lung cancer, but it doesn’t invalidate DLL3 as a target. The BiTE molecule, AMG 757, showed a response rate of 14%, which seems low, but 20% were ongoing at 6 months and some of these went out past a year. With more data, those numbers will increase. Primary toxicity of concern is cytokine release syndrome [CRS]. Those were low grade in the trial. As that study increases, as more patients go on, we can see if that toxicity demonstrates tolerability. There is also a DLL3 CAR [chimeric antigen receptor] T molecule that was in development. That trial is not accruing now, and we’ll wait to see the reason for that and early results from both of these studies, which are important approaches exploiting that selective expression of DLL3.

Jared Weiss, MD: In the short run, meaning the next few years, small cell lung cancer is probably going to be more stable than dynamic. We have a number of trials coming down the pike that might change the standard of care in the period maybe just beyond that, and I’ll start with those. We just saw data at World Lung [the World Conference on Lung Cancer] on second-line liposomal irinotecan. There was a 20% rate of grade 3/4 diarrhea, 16% rate of grade 3/4 neutropenia. Efficacy data are limited. We only saw 25 patients treated at the recommended phase 2 dose. But in this limited sample, the response rate was promising at 44%. PFS [progression-free survival] there was 4 months and OS [overall survival] 8 months.

We also saw at World Lung data on apatinib plus chemotherapy. Here the chemotherapy is dealer’s choice of irinotecan or docetaxel; we saw a response rate of 25%, PFS of 7 months, and overall survival of 12.5 months. Again, only 31 patients here. There we saw some neutropenia, hypertension, and hand-foot syndrome. What was nice is we did get a dose out of that phase 1 study. We saw data at World Lung on AMG 757, which is a BiTE directed against DLL3. The CRS rate here was 44%, but most of them were low grade and easily managed, only 2% of them were high grade. The response rate was 14%, perhaps a bit higher as you got up to the higher doses, and the median duration of response was only 6 months.

Finally, we saw data on lurbinectedin in combination with irinotecan in relapsed small cell. There we saw data on 21 patients. The toxicity was perhaps acceptable but very real, 24% grade 3/4 fatigue, 29% high-grade diarrhea, 62% neutropenia. The response rate was good at 62%, 50% in those with a chemotherapy treatment-free interval of less than 90 days, 69% in those of at least 90 days. Frankly, for lurbinectedin, I’m much more excited about the single-dosing strategy that I already have access to, and I’m interested in strategies to optimize dose with single agent.

Looking past this immediate timeframe of a few years, I’m particularly excited about cellular therapeutics against extensive-stage small cell lung cancer. I would highlight as the 2 targets with most immediate promise, DLL3 and GD2. Looking further down the road than that, I’m impressed by thetranscription-based subtyping of extensive-stage small cell. I see very distinct biologic themes, and while these may have no impact on current treatment decisions and are not obtained as part of standard of care, the themes biologically are sufficiently distinct that I see high promise for these ultimately improving care and leading to novel therapeutics, and perhaps selection of patients for therapeutics.

Transcript Edited for Clarity