Actionable Mutations in NSCLC: Expert Perspectives in Testing and Targeted Therapy - Episode 7

Updates in Treatment of HER2 Mutant NSCLC

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Dr Misako Nagasaka reviews clinical trial data presented at ESMO 2021 on therapies for NSCLC harboring HER2 exon 20 mutations.

Ben Levy, MD: Let’s shift gears to HER2 exon 20, which isn’t to be confused with EGFR exon 20. Not all HER2 is exon 20, but most are. Misako, do you want to walk us through this? We’ve got some very exciting data coming down the pike for these mutations. Walk us through where we’re at with some of the drugs that are emerging as potential therapeutic strategies.

Misako Nagasaka MD, PhD: Sure. There are 2 important studies in this space. In particular, the DESTINY-Lung01 trial is potentially practice changing. DESTINY-Lung01 was a multicenter, 2-cohort phase 2 trial enrolling patients with HER2-mutant or -overexpressed non–small cell lung cancer refractory to standard treatment to receive [fam-]trastuzumab deruxtecan[-nxki], or T-DXd, which is an ADC [antibody-drug conjugate] with 3 components—the humanized anti-HER2 IgG1 mAb [monoclonal antibody], the topoisomerase I inhibitor payload and exatecan derivative, and a tetrapeptide-based cleavable linker.

The primary end point was objective response rate per RECIST version 1.1 by independent central review [ICR]. The initial presentation of the preliminary results [occurred] at ASCO [American Society of Clinical Oncology Annual Meeting] 2020, and the updated primary analysis results from the HER2-mutant cohort of the DESTINY-Lung01 study were reported as a late-breaking presentation at ESMO [European Society for Medical Oncology Congress] 2021 and simultaneously published in the New England Journal of Medicine. The total number of patients reported was 91. In patients who have progressed following 1 or more systemic therapies, the confirmed objective response rate by ICR was 54.9%. Disease control rate was 92.3%, with a median duration of response of 9.3 months, median PFS [progression-free survival] of 8.2 months, and a median OS [overall survival] of 17.8 months.

Any treatment-related adverse events [TRAEs] were seen in 96.7% of patients, with grade 3 or higher TRAEs at 46.2%. Importantly, the adjudicated drug-related ILD [interstitial lung disease] was seen in 26%. Of the 26%, approximately 19.8% had grade 1 or 2, and approximately 6.6% had grade 3 or higher. The efficacy results—with the objective response rate of 54.9%, median PFS of 8.2 months, and median OS of 17.8 months—are certainly promising, but I feel that more data will be helpful to identify patients at risk for developing AEs, in particular ILD.

The other important study to highlight in this space is the ZENITH20 trial using a TKI [tyrosine kinase inhibitor], poziotinib, for patients with HER2 exon 20 mutations. ZENITH20 is a global, multicohort phase 2 study. Cohort 4, which enrolled first-line patients with non–small cell lung cancer with HER2 exon 20 insertion mutations, was just presented at ESMO Targeted Anticancer Therapies Congress 2022. The primary objective was objective response rate per RECIST by ICR. In a total of 70 patients, there was an objective response rate of 41%, a disease control rate of 73%, a median duration of response of 5.7 months, and a median PFS of 5.6 months. Of note, 48 patients took 16 mg [daily], and 22 patients took 7 mg [twice a day].

Grade 3 or higher adverse events were reported in 69% of patients. The common ones included rash, dermatitis, and diarrhea. While the safety profile was consistent with the TKI class, the tolerability, dose reduction, and interruptions were reported to be improved with the [twice-daily] dosing.

Ben Levy, MD: Misako, you elegantly reviewed both of these trials. How do you treat a patient who has a HER2 mutation? I assume you’re testing with comprehensive genomic profiling and identifying these. Trastuzumab deruxtecan is potentially one that could be approved. We didn’t get a chance to talk about T-DM1 [ado-trastuzumab emtansine]. That’s another ADC targeting HER2. How do you treat these patients?

Misako Nagasaka MD, PhD: I try to put these patients on clinical trials whenever available. But if none are available, I’d do platinum-based chemotherapy up front because the current data for the DESTINY-Lung01 study is post–first-line standard-of-care platinum-based therapy. I’d be willing to use trastuzumab deruxtecan in the second line. It’s on the NCCN [National Comprehensive Cancer Network] guidelines with T-DM1, as you just mentioned. I have used afatinib in patients with HER2 mutations when the performance status was borderline or when I thought chemotherapy was challenging.

Ben Levy, MD: This is the challenge. I’ve fortunately been able to use trastuzumab deruxtecan on clinical trial. My experiences mirrored what we’ve seen in the trials. The response rate is north of 50%. Some of these are very durable. We haven’t had time to talk about intracranial activity of these potential drugs, these new drugs, these ADCs. We don’t know. The molecule is quite large, so theoretically and scientifically, it shouldn’t elicit responses in the brain. But this is what we’re looking for. I also had the opportunity to use poziotinib. Misako, I don’t know whether you’ve used that drug. Do you have any thoughts on that?

Misako Nagasaka MD, PhD: It’s the exact same situation as yours, Dr Levy. I have clinical trial experience with both trastuzumab deruxtecan and poziotinib, and some of my patients experienced both. My personal impression is that trastuzumab deruxtecan is basically chemotherapy given in a targeted fashion. You need to monitor for cytopenias and your usual chemotherapy adverse effects like nausea, vomiting, and hair loss. Poziotinib, on the other hand, is an oral option. While patients like having oral options, this drug is pretty challenging in the sense that there are very high rates of high-grade rash and diarrhea. It’s very difficult to adjust the dose, hold, and be in close communication with patients. Your nurses have to be aware of all of these issues. It’s doable, but it isn’t that easy.

Ben Levy, MD: Yes, it isn’t the easiest to get people through.

Misako Nagasaka MD, PhD: No. But the [twice daily] dosing is potentially a little better, and that’s promising—although the ZENITH20 cohort 4 presentation was for the first line, and the response rate was only 40%, if I’m remember the data correctly. I understand that the number of patients was still limited. But with this amount of toxicity, we have to balance out the efficacy. It’s a tough field.

Ben Levy, MD: Yes. That was a nice overview. We still have a lot of unanswered questions for this genotype. My hope is that trastuzumab deruxtecan gets approved very soon, and we can leverage it. I’d like to see it used in the first line. It’s a pretty good drug. Obviously, the ILD that you mentioned can be a challenge.

Transcript edited for clarity.