Reviewing Evidence for Therapies in NSCLC With EGFR Exon 20 Insertion

Zofia Piotrowska, MD, MHS

Assistant Professor of Medicine

Harvard Medical School

Medical Oncologist

Massachusetts General Hospital Cancer Center

Boston, MA

Targeted Oncology^TM: What data supports the use of mobocertinib (Exkivity) in patients with non–small cell lung cancer with an EGFR exon 20 insertion?

ZOFIA PIOTROWSKA, MD, MHS: Mobocertinib is the oral EGFR inhibitor that was tested in a phase 1/2 study [NCT02716116], which included dose escalation and [several] different expansion cohorts, including all patients with EGFR exon 20 insertions. Ultimately, the approval was based on this platinum-pretreated patient cohort, which included 114 patients who were drawn from the phase 1 and from the dose escalation [n = 6], dose expansion [n = 22], and from the EXCLAIM extension cohort [of previously treated patients with EGFR exon 20 mutations; n = 86].¹ So these were all patients with EGFR exon 20 insertions who had received prior platinum-based chemotherapy and received mobocertinib at the recommended phase 2 dose [RP2D] of 160 mg daily.

In this population of 114 patients, one thing to highlight about the demographics is that many of these patients were heavily pretreated. The number of prior regimens [was greater than 3 for 27% and was 2 for 32%]. As you might expect, the majority of these patients were never-smokers or former smokers, very few [n = 2] current smokers. In terms of past systemic therapy, all of these patients had prior chemotherapy and about half had prior immunotherapy. About 35% of them had baseline brain metastases, which is highlighting that these patients are certainly at risk of brain metastases as we might expect for an EGFR-positive lung cancer population.

What are the efficacy and safety data for mobocertinib in this platinum-pretreated cohort?

The objective response rate [ORR] was 28% by blinded independent review committee [IRC] and 40% by investigator review. The median duration of response [DOR] on the study was 17.5 months and the median progression-free survival [PFS] was 7.3 months. The breakdown of responses [showed there were no complete responses], and the other thing I’ll highlight is [the investigators-assessed ORR] by the different types of EGFR exon 20 insertions. There is not a clear signal that one [category] responds better than another. I think maybe in the future we might hone in on the specific region where the insertion occurs, but for now it’s enough to just recognize the exon 20 insertions. Median overall survival [OS] was 24 months.

[In terms of] safety, this is an oral EGFR inhibitor, and many of the toxicities are ones that we might expect from an oral EGFR inhibitor. I will highlight that 91% of these patients experienced diarrhea, about 21% of them are grade 3 or higher, 45% of the patients had rash, and 38% had paronychia but this was all low grade. There was some anorexia [35% any grade] and nausea [34% any grade]. A few special considerations that are important to be aware of include QT prolongation, which can be a risk factor with this drug; 11% of patients had it. Cardiomyopathy was seen in 2.7% of the patients, and then about 4% had interstitial lung disease. I think these will seem familiar from other EGFR inhibitors, but it’s important to keep in mind. Then if you look at the rates of dose reduction, 25% of patients had a dose reduction from the RP2D of 160 mg daily, and 17% of the patients discontinued treatment due to toxicities.

Is an echocardiogram needed before starting patients on mobocertinib due to the cardiac toxicities?

The guidelines are to do it in patients with cardiac risk factors, which isn’t specifically defined, so I have tried to get one at baseline for patients, even if they [only] have [an issue like] hypertension. There is not clear guidance as to how to monitor them. But I think similar to what I might do with osimertinib [Tagrisso], [check] once every 6 months or a year. Certainly if they have any respiratory symptoms, [get an echocardiogram] because it can happen and it can be devastating if you do see it. So if you have patients with cardiac risk factors, it’s important.

What led to the approval of amivantamab (Rybrevant) in this setting?

Amivantamab has a different mechanism of action [from mobocertinib]. This is an intravenous infusional antibody targeting EGFR and MET. It’s a bispecific antibody….The approval for amivantamab came from the phase 1 study called the CHRYSALIS trial [NCT02609776], which included the dose escalation and then established the RP2Ds that are based on weight [1400 mg for patients who weigh at least 80 kg, 1050 mg for patients who weigh less than 80 kg]. Cohort D included patients with EGFR exon 20 insertions.²

There were 81 patients with EGFR exon 20 insertions, and the demographics are pretty similar to what we saw in the other study. Patients received a median 3 prior lines of therapy. Very few patients had other EGFR exon 20 insertion–targeted agents because these were not available when the study was performed. Similar to the mobocertinib data, all patients had received prior chemotherapy.

Please describe the results of the CHRYSALIS trial.

The overall response rate was 40% by blinded IRC review and 36% by investigator review. The median DOR was 11 months, median PFS was 8.3 months, and the median OS was 22.8 months. [Investigators analyzed response based on the] type of insertion. There is a slight hint here that the near-loop insertions may have a little bit higher response rate, but they’re also a bit more common. It’s hard to make too much of that for now, so we’ll have to stay tuned for that.

In terms of toxicity, this is a different drug [than mobocertinib] with a different route of administration and different toxicity profile. One of the most common toxicities was rash, which was seen in 78% of patients treated at the RP2D, largely low grade but still fairly common. Importantly, 65% of these patients had infusion-related reactions, which were mostly grade 1 or 2. These tend to occur with the first infusion, and there are guidelines in the amivantamab dosing for split dosing over day 1 and day 2 with the first infusion, glucocorticoid premedications, and some other guidelines. That is important to be aware of. Paronychia was also seen. Some patients also had hypoalbuminemia and edema which are likely related to the MET effects of this agent. Overall, there were not [a lot] cardiac toxicities. There was very little pneumonitis, just in a few percent of patients.

If you look at dose reductions, about 10% of patients at the RP2D and 7% of all patients had to discontinue due to adverse events, and I think that’s relevant because if you think about the 65% of patients who had infusion reactions, one important thing to know is that even patients who have an infusion reaction can usually be treated through it. The split dosing helps mitigate that, and even patients who react can then go on to receive subsequent infusions. I’ve heard it compared with rituximab [Rituxan] reactions more than paclitaxel hypersensitivity or something like that.

How would you summarize the 2 targeted agents for EGFR exon 20 insertions?

Amivantamab is a bispecific antibody targeting EGFR and MET. It’s infusional. It requires weekly infusions for the first 4 weeks with split dosing of the first 1 and then every 2 weeks. With mobocertinib, the advantage is that it’s an oral medicine; it comes in 40 mg capsules with a starting dose of 160 mg daily. In terms of toxicities, gastrointestinal and skin toxicities are the most common ones for both agents.

_REFERENCES

_{1. Riely GJ, Neal JW, Camidge DR, et al. Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations from a phase I/II trial. Cancer Discov. 2021;11(7):1688-1699. doi:10.1158/2159-8290.CD-20-1598}

_{2. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662}