Discussing Data on Efficacy and Adverse Events of Mobocertinib for NSCLC

Gregory Riely, MD, PhD (Moderator)

Vice Chair of Clinical Research, Department of Medicine

Memorial Sloan Kettering Cancer Center

New York, NY

DISCUSSION QUESTIONS:

• What is your reaction to the data from the phase 1/2 trial (NCT02716116) of mobocertinib (Exkivity) after platinum-based chemotherapy?​
• What stood out to you in terms of efficacy and safety? ​

MAURA HAGAN, MD: Is there a recommendation to routinely check ECGs, given that there’s an 11% rate of QTc prolongation?¹ Because I’ve not done that.

GREGORY J. RIELY, MD, PHD: I think it’s similar to the osimertinib [Tagrisso] label.

HAGAN: I don’t think I did it there either.

RIELY: Yes, there’s definitely a role for following [this]. With the rate of cardiomyopathy for both drugs, there’s occasional ECGs for evaluation and it is always clinically indicated.^2,3 But I’ll admit that those are lower on my priority list for most of these patients.

PAUL UNGER, MD: You always want your waterfall plot to look as [the one in the trial of mobocertinib] did. Even if the overall response rate [ORR] is, in a sense, more modest, that waterfall plot from a palliative treatment standpoint is pretty compelling—notwithstanding the adverse events which can usually be managed with dose reductions and other things.

RIELY: I think that’s exactly right. That 28% ORR is a sobering number, but I think we would all say that that 28% with that waterfall plot is way better than the 20% ORR with docetaxel or something else like it in this context.

QAMAR ZAMAN, MD: How many patients needed dose reduction or dose interruptions?

RIELY: Certainly some proportion of patients did require dose reductions [n = 29, 25% in the platinum-pretreated patients cohort].¹

ZAMAN: A lot of us are used to managing diarrhea from tyrosine kinase inhibitors, especially if you treat any breast cancer and you have abemaciclib [Verzenio] and things like that. But sometimes, like what I do with regorafenib [Stivarga], I may dose escalate instead of dose reduce if I know someone is a little bit older and frail and may end up with renal issues with dehydration and not follow directions. So I might start off with a 50% dose and then escalate, but it just depends on the patient.

RIELY: I think the other big thing with these toxicity events is the early management, so when talking about the diarrhea, making sure they get the loperamide before they start taking it, making sure that they are aware of this. We want them to call us to talk about toxicities as soon as possible. The alternatives are not good when they stop taking the medicine because they don’t like the toxicity, or they continue and find themselves with 8 to 10 bowel movements a day and [end up in the] emergency department with a creatinine level of 2.5 mg/dL.

DISCUSSION QUESTION

• What are your thoughts concerning the data from the phase 1 CHRYSALIS trial (NCT02609776) of amivantamab (Rybrevant)?

MARK DRUCK, MD: Was the [3%] rate of grade 3 or higher infusion reactions [to amivantamab] with intravenous [IV] premedications?⁴

RIELY: [We] haven’t identified a good premedication to prevent infusion-related reactions. It is a thing that only happens once…they get the infusion, [then] they get a reaction. We get…everybody involved to make sure that they get the right supportive medicines, and then you stop the medicine, they go home, they come back the next day and they get it, no problem. There’s no infusion-related reaction, for the most part, the next day or with any of the other doses. Nobody has found a good premedication to prevent that infusion-related reaction, but it’s generally just the first time.

DISCUSSION QUESTIONS

• During shared decision making, how do you talk about the 2 options?​
• ​ How should toxicities associated with these agents targeting EGFR exon 20 insertions be monitored, mitigated, and managed?

RIELY: As we think about these agents—amivantamab, mobocertinib, 2 FDA-approved agents for patients with EGFR exon 20 insertions—does anything stand out in terms of how you use pick which drug to use?

PRABHSIMRANJOT SINGH, MD: I think this is a great time to be treating lung cancer because we have these 2 drugs available when looking for 1. The way I look at these data is both drugs are great in a sense of what the patient is going to be up for. Are they able to take the medications? Are they compliant? There is always the question about co-payment on oral drugs, which is also sometimes a big issue when patients are taking the oral drugs. Mobocertinib falls into the category of a newer version of osimertinib and amivantamab is a combination of monoclonal antibodies with infusion-related reactions, which are well tolerated. I’ve given it in clinical trials. For patients who are frail, oral treatment is not that great. There is concern about toxicity. Usually, we prefer to give them IV, just so that we can monitor them if they are able to come to our infusion center. During the time of COVID-19, oral drugs were a blessing.

RIELY: That’s a good distinction. I think the IV medications are particularly good in the frailer population because you have to see them. I think we’re all a little afraid of what could happen when we hand them a bottle of pills that could cause some trouble.

MARK DRUCK, MD: As a general oncologist who treats everything, nowadays more and more I’m going to give a drug that I will not [need to] give for another 2 years. I’ve always considered infusion reactions an unacceptable toxicity to me and my staff. It causes a lot of blood pressure problems. When I see a grade 3 infusion reaction, I suspect they’re going to go the hospital, whether they’re going to the intensive care unit or they’re just going to the hospital but [for this 3% of patients with grade 3 or higher infusion reactions]…these are real issues for the staff and for the physicians. This has nothing to do with the science and the response rates, which are probably better with the IV drug [amivantamab]. But I must tell you, when I look at the NCCN [National Comprehensive Cancer Network] guidelines and I’m deciding what drug to give in this situation, I would probably not give it because of the IV, especially if [I am told that it depends on] a lot of luck. That is probably the most serious AE, in my mind. I can deal with all the others.

RIELY: I think there is a real issue around feeling comfortable. We all got used to giving paclitaxel [Taxol], but we never liked it. And then when we could avoid it, we did. This has got the flavor of paclitaxel reactions, but it’s a thing that never comes back after the first episode. But I hear you because they are disruptive.

DRUCK: That takes a lot of guts to bring [the patient] back the second day [for IV infusion]. I don’t know who has more guts, the patient coming back the next day or the physician meeting them at the office.

RIELY: I wasn’t involved in the clinical trial for amivantamab, but I think whoever decided to try again deserves some credit.

_REFERENCES

_{1. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761}

_{2. Exkivity. Prescribing information. Takeda Pharmaceuticals; 2021. Accessed November 14, 2022. https://bit.ly/3TB49Jm}

_{3. Tagrisso. Prescribing information. AstraZeneca Pharmaceuticals LP; 2020. Accessed November 14, 2022. https://bit.ly/3GaqVVD}

_{4. 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}