Amivantamab/Lazertinib Maintains OS Benefit in EGFR+ NSCLC

Joshua K. Sabari, MD

Assistant Professor, Department of Medicine

NYU Grossman School of Medicine

Director, High Reliability Organization Initiatives

Perlmutter Cancer Center

New York, NY

Targeted Oncology: What takeaways do you have from the use of subsequent therapies in the MARIPOSA-1 trial (NCT04487080) in patients with EGFR-mutated non–small cell lung cancer (NSCLC)?

Joshua K. Sabari, MD: Time to second progression [PFS2]…is important because if you have therapies that are active in a later-line setting, do getting the therapies in sequence matter?

PFS2 had an HR of 0.75 [95% CI, 0.58-0.98; P = .03], so there's still a major difference between amivantamab [Rybrevant] and lazertinib [Lazcluze] vs osimertinib [Tagrisso], with 72% PFS2 free at 2 years vs 64% with osimertinib.¹ The most common therapy at first subsequent progression…for those receiving amivantamab/lazertinib was 49% receiving EGFR-TKI [tyrosine kinase inhibitor] monotherapy…and 33% received chemotherapy alone. A lot of patients don't go on to get second-line therapy, so using our best therapy up front is a common thing that we teach our fellows and our residents.

[In the osimertinib arm], EGFR TKI monotherapy, at 27%, was probably mostly gefitinib [Iressa] or erlotinib [Tarceva] or continuing the third-generation EGFR-TKI post progression. That is what's available. Chemotherapy alone [was used next in] 39% in the osimertinib arm. But think about in your clinic when you have a patient [experiencing progression] and they're not well, how often do you say, “Let's not start chemotherapy, let's irradiate and just continue osimertinib?” That would be included in this patient population here, so that's important to think about in the real-world setting.

What other key efficacy end points were reported in this trial?

When we look at the MARIPOSA-1 primary results, [in terms of] objective response rate [ORR] and duration of response [DOR], one of the important things here is that there is no difference in the ORR. For amivantamab/lazertinib, it's 86% and for osimertinib it's 85%, so there are similar response rates in the front line. This is better than what we saw [for osimertinib] in FLAURA [NCT02296125].

The DOR is different. The Kaplan-Meier curves overlap for the first 6 months, and then they separate, and they remain separated throughout. There is a median of 25.8 months DOR for amivantamab/lazertinib vs 16.8 months for osimertinib alone. I think this is the most important and we look forward to seeing some updated data.

Looking at the further overall survival [OS] analysis, what we had initially was a 0.80 HR.¹ It's now down to 0.77 [95% CI, 0.61-0.96; P = .019], and hopefully this will continue to improve.² But if you look out at 36 months or 3 years, 61% of patients are alive who received amivantamab/lazertinib vs 53% who received osimertinib. A lot of us wait to see full OS data…these data are still maturing, but clearly there is a trend towards positive OS, something that we've seen clearly with osimertinib [in FLAURA], 38.6 months vs 31 months [median for gefitinib or erlotinib], but we have not yet seen it for [osimertinib plus chemotherapy in] FLAURA2 [NCT04035486].³

So, 53% are [alive with osimertinib with a median OS of] 37.3 months, very similar to what we saw in FLAURA, so that reassured me.² Median OS is not yet reached for amivantamab/lazertinib, and this is at a median follow up of 31.1 months. We hope to see updated data with full analysis.

Looking at intracranial progression-free survival from the updated data for amivantamab/lazertinib, at 36 months, there is a sustained benefit for amivantamab/lazertinib at 38% intracranial progression free vs 18% for osimertinib alone.² These are 3-year landmark data. We hope to see further data, and there is a lot of discussion about osimertinib having phenomenal central nervous system penetration. It was exciting for us to see an improvement upon that with the addition of amivantamab to lazertinib, and these are some of the longer-term intracranial activity data that we have in the combination setting to date.

Are there approaches to mitigating the adverse events of concern with amivantamab and lazertinib?

We've been able to mitigate infusion-related reaction, and we're able to monitor and manage it. After cycle 1 day 1, the rate of infusion reaction goes below 2% and hopefully, with the subcutaneous formulation in the future, we'll get rid of this. Deep vein thrombosis prophylaxis is an issue, but we're able to anticoagulate these patients. For me, it hasn't been a major issue. In the recent data we presented for PALOMA-3 [NCT05388669], we show that with prophylactic use of anticoagulation, the toxicity profile in the sense of venous thrombotic events [VTEs] is very similar between the different arms, osimertinib alone vs amivantamab/lazertinib.⁴

But the rash is a major issue with this therapy, and it's one of the more chronic toxicities. Both therapies [are probably responsible]; they both have EGFR inhibition, but amivantamab probably has more EGFR wild-type inhibition than lazertinib. Lazertinib was pretty EGFR mutant-specific. In my own experience, they complement each other, but I think most of it is being driven by amivantamab.

Most of the VTEs are grade 1 and 2, and grade 4 and 5 VTEs are less than 1% and comparable in both arms.¹ In general, patients with EGFR-mutant lung cancer have higher rates of VTE but when we add amivantamab to lazertinib, there is a 3-fold higher risk. I think anticoagulating patients is important.

With CNS metastases, I usually talk to my neuro-radiation oncologist and my neuro-oncology team; most of the time, 99% we feel very confident anticoagulating patients unless they have a very large brain metastasis that is hemorrhagic. In that case, we usually resect up front. We don't like to do GammaKnife or any other stereotactic radiosurgery in that patient population. But for smaller metastases, there are a lot of data supporting safe use of anticoagulation.

You need to give some time post resection, 2 weeks to 2 months. It's very dependent on neurosurgery. Some neurosurgeons want platelets above 100,000/μL, some want 50,000/μL, some say no anticoagulation for 3 months. One to 2 months is the standard recommendation for neurosurgeons.

What do you think is a mechanism for action for VTEs?

We don't have a clear answer. EGFR can be expressed in multiple tissues, and we know cancer in general is a prothrombotic event. Why with the addition of amivantamab and lazertinib, do we see increased thrombosis? I initially thought it might have to do with the infusion-related reaction and inflammation caused up front. But when we look at the subsets of patients, those who had the infusion-related reaction and those who don't, it does not differentiate the rates of VTE. So, it has to do something with…epithelial injury or endothelial injury up front. It's not a clearly known mechanism as to why that is, but clearly, when we anticoagulate, we reduce that difference, so it's equal in both of the patient populations.

_References:

_{1. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062}

_{2. Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. J Thorac Oncol. 2024;19(suppl 10):S10-S11. doi:10.1016/j.jtho.2024.09.026}

_{3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662}

_{4. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605. doi:10.1200/JCO.24.01001}