Novel Therapies for NSCLC

Ben Levy, MD: We’ve had some data that have come out of ASCO [American Society of Clinical Oncology annual meeting] this year, 2 sets of data, that we’ll review. These are novel therapies. The first is amivantamab with lazertinib. The other is the HER3 DX [deruxtecan] drug. Alex, you were senior author on the amivantamab/lazertinib data. Walk us through that data and then after that, if you could, talk to us about the HER3 DX drug as well.

Alex Spira, MD, PhD, FACP: Amivantamab, just approved for exon 20, has a couple of different goals and roles as it’s evolved over time. It’s the monoclonal antibody. For those of you who don’t remember, it’s a monoclonal antibody against MET and EGFR. Again, just approved for exon 20. But this study is not in exon 20. This is post-EGFR therapy as a next treatment. This was combined with lazertinib, and lazertinib is essentially equivalent to osimertinib. It was probably left on there because AMI [amivantamab] as the monoclonal doesn’t have much CNS [central nervous system] penetration.

It’s an effort to keep the CNS effects on with lazertinib but adding a monoclonal against EGFR. This is a straightforward study, nonrandomized. These are all patients who progressed previously on OSI [osimertinib] therapy. The bottom line is a 36% response rate with a significant number of patients remaining on study at the time of follow-up, which is about 8.2 months. They looked at a couple of different things. Clearly in the back of everyone’s mind, there are multiple ways to develop OSI [osimertinib] resistance, the most common C797S, as well as c-MET amplification, hence the design of the drug.

They looked; in the patients who were what we call biomarker-positive, there was a higher response rate, 47%. Those patients who had a secondary EGFR mutation, or MET amplification, or exon 14 skipping go along with the biology of the drug. On the other hand, if you didn’t have this, there was still a 29% response rate. Again, small numbers, so not much to go about how much the difference really is. But nevertheless, there does appear to be activity regardless of your positive markers.

On the other side, they came up with a new way to look at things, and these are looking at people that were either EGFR or MET-high. This is not something we really think about. You know we don’t think about high IHC-high [immunohistochemistry-high] patients for EGFR. We’ve thought about it for MET before. But for those patients who had a subsequent biopsy that was high for these, they had a 90% response rate, perhaps developing a biomarker to see who may or may not respond in this patient population. Now again, the take-home is there were only 10 patients in that latter cohort. This is clearly an active combination and appears to work, not a ton of toxicity. The study is ongoing, and we’ll learn more. Obviously, with the biomarkers, we’re super hopeful that we’ll get a lot more information going forward as to who may and may not benefit.

The other study I mentioned is patritumab [deruxtecan], which is an anti-HER3. We don’t think about HER3 in the EGFR cohort but there have been data before. We’ve seen some preliminary data. This update was published by [Pasi] Janne, [MD, PhD,] from the Dana-Farber [Cancer Institute]. In essence, these are patients who progressed on osimertinib before. They had to have progressive disease. In a nutshell, 57 patients were treated with this antibody-drug conjugate at the dose of 5.6 mg IV [intravenously] every 3 weeks. The median number of regimens was 4, so they were heavily pretreated. All had a prior TKI [tyrosine kinase inhibitor], 91% had platinum-based therapy, as one would expect. Confirmed overall response rate by a blind review was 39%, and most of these occurred within 3 months of starting. They looked at multiple ways of mutation by next-generation sequencing in blood and worked across all cohorts.

This antibody-drug conjugate platform has been well studied. We’ve seen it with trastuzumab, we’ve seen it with datapotamab, and we’ve seen all the [adverse] effects, thrombocytopenia, neutropenia, fatigue. ILD [interstitial lung disease] is the big [adverse] effect in this antibody-drug conjugate that’s concerning; 7% had drug-related ILD. It appears to be an active drug. It appears to work across the board, and excitingly, it looks like we’re developing multiple different pathways to overcome first-generation OSI [osimertinib] resistance.

Ben Levy, MD: Yes, I’m encouraged by both data sets, and perhaps we’ll start to move the needle in the resistant setting with both of these drugs. The median line of therapy for the HER3 DX drug was 4; these were patients who received a median 4 lines of therapy. With a response rate close to 40%, it’s remarkable.

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