Seattle-based Clinicians on Effective Treatment Combos in EGFR-Mutated NSCLC

A panel of experts met to discuss the best treatment options for patients with EGFR or TP53-mutated non–small cell lung cancer.

A Satellite Session hosted in Seattle, WA, focused on various treatment options that would best benefit a patient with EFGR and TP53 mutations. The panel mainly focused on treatment with either osimertinib (Tagrisso) monotherapy or the combination use of lazertinib (Lazcluze) plus amivantamab-vmjw (Rybrevant) and how those would be the best options to help treat a specific patient case study.

The panel was led by Sid Devarakonda, MD, director for Thoracic Medical Oncology at Swedish Cancer Institute and clinical associate professor at Elson S. Floyd School of Medicine at Washington State University. Additional panelists included Anish S. Konde, MD, a medical oncologist at Providence South Sound Group; Perrin E. Romine, MD, a medical oncologist from Swedish Cancer Institute Medical Oncology in Edmonds; Kelly G. Paulson, MD, a medical oncologist from Swedish Cancer Institute Medical Oncology in Edmonds; Elizabeth F. Mcgehee, MD, a medical oncologist from Swedish Cancer Institute Medical Oncology in Edmonds; Carly Irwin, BScN, a clinical nurse coordinator from Swedish Cancer Institute Medical Oncology; Bin Xie, MD, a medical oncologist fromSwedish Cancer Institute Medical Oncology in Issaquah; Eileen M. Johnston, MD, a medical oncologist from Swedish Cancer Institute Medical Oncology in Edmonds; and Jay P. Lopez, MD, a medical oncologist from Swedish Cancer Institute Medical Oncology in Edmonds.

The phase 3 MARIPOSA trial (NCT03778957) assessed amivantamab plus lazertinib (n = 429) vs osimertinib monotherapy (n = 429) vs lazertinib monotherapy (n = 216).1 The primary end point was progression-free survival (PFS) by blinded independent central review. Secondary end points included overall survival, objective response rate, and duration of response. This regimen was also approved by the FDA in August 2024.2

The median PFS in the combination arm was 23.7 months (95% CI, 19.1-27.7) vs 16. 6 months (95% CI, 14.8-18.5) in the osimertinib arm (HR, 0.70; 95% CI, 0.58-0.85; P <.001). At 12 months, 73% of patients in the combination arm were progression-free vs 65% in the Osimertinib arm. Rates at 24 months were 48% vs 34%, respectively.

The overall response rate in the combination arm was 86% (95% CI, 83%-89%) vs 85% (95% CI, 81%-88%) in the osimertinib arm, with 80% (95% CI, 76%-84%) vs 76% (95% CI, 71%-80%) of confirmed responders. Complete responses were noted in 7% vs 4%, partial response in 79% vs 81%, and stable disease in 7% vs 10%. The median duration of response was 25.8 months (95% CI, 20.1-not eligible) in the combination arm and 16.8 months (95% CI, 14.8-18.5) in the osimertinib arm.

The median intracranial PFS was 24.9 months (95% CI, 20.1-34.7) vs 22.2 months (95% CI, 18.4-26.1) in each arm, respectively (HR, 0.82; 95% CI, 0.62-1.09; P = .165). At 24 months, 51% vs 48% of patients were progression-free intracranially vs 38% vs 18% at 36 months.

Regarding adverse effects (AEs), the most common AEs were observed during the first 4 months and declined over the next 4 months. Of note, rash decreased by about 50%, paronychia by about 30%, and diarrhea by about 70%. There were no grade 4 or 5 AEs reported.

Patient Case

• Diagnosis:
  • A 62-year-old patient with a cough and shortness of breath on exertion of 3 months duration, of which the patient noticed gradual worsening.
  • Chest X-ray by the primary care provider showed a right upper lung (RUL) mass. The CT scan showed a 7.5 cm mass in RUL with partial collapse of RUL and ipsilateral mediastinal lymph node enlargement. The staging showed liver metastases and 3 asymptomatic 4 to 5 mm brain metastases.
  • The patient underwent a bronchoscopy. The biopsy from RUL showed moderately differentiated adenocarcinoma. The patient had a PD-L1 of 80%; next generation sequencing showed an EGFR exon 21 L858R mutation with a concurrent TP53 mutation.
• Treatment options included:

1. Osimertinib
2. Afatinib (Gilotrif)
3. Lazertinib plus amivantamab
4. Carboplatin plus pemetrexed and osimertinib for 4 cycles followed by osimertinib plus pemetrexed maintenance
5. Osimertinib plus bevacizumab (Avastin)

• Discussion
  • Lazertinib plus amivantamab was chosen for this patient. What are some strategies used in practice for managing treatment-related adverse effects (AEs) for patients on this regimen?

Devarakonda: Let me ask you one question. What do you make of the TP53 [mutation]? Does that raise [concerns] a bit? What are your thoughts on whether you care about the L858R [mutation] vs an exon 19 deletion, if those are factors you even worry about?

Konde: The TP53 [mutation] just raises my radar level almost. I think of these patients as somebody who tends to have a poor prognosis. Apart from that, clinically speaking, I wouldn’t differentiate L858R or an exon 19. I just have my guard up high, so to speak. Osimertinib is a fine choice. I’d be curious to see what everybody would pick rather, I suppose.

Devarakonda: Perrin, what would you do?

Romine: I was talking with one of my old mentors about this recently, and he was [saying osimertinib] was just going to be more for incremental benefit and more toxicity. The short answer is there is more data now for upfront combinations, but you have to be cautious about what you are getting from that. This is a 62-year-old who was relatively asymptomatic from his metastatic sites. To your earlier question, I do think of L858R and TP53 mutations as higher-risk diseases. Those are patients who may benefit more from a more aggressive regimen, but I just don’t know how much you’re going to get. Those are my thoughts.

Devarakonda: Kelly, your thoughts?

Paulson: Well, if the only thing was survival, that would be a different piece than the quality [of life] piece.

Devarakonda: It’s a package deal, right?

Paulson: It’s a package deal. I would have an engaged conversation with a patient about choosing between [options] 1, 3, and one of the many clinical trials for EGFR frontline [treatment]. The [lazertinib] went fine in the patient, but you and I both had some gnarly amivantamab [reactions] recently.

Mcgehee: I have one too.

Paulson: We’re putting those together. There’s a lot of right answers here now, and so it’s an interesting space to talk about because it’s a lot of shifts. [Option] 4 also wouldn’t be wrong, but [there are some downsides]. Plus, it takes out the regimen that you get the checkpoint inhibitor down the road, and so that also would make me like [option] 1 or 3 better.

Mcgehee: I will say I do have a patient who was diagnosed like a lot of these patients end up through the hospital, and so there is a required delay between diagnosis and being able to get that EGFR [testing]. I had a woman originally from Hong Kong who was a never smoker. I had high suspicion for an EGFR mutation, but I needed to wait on it, she didn’t need treatment, and she got carboplatin plus pemetrexed to start, and she tolerated it well, so we added in osimertinib, and she’s on osimertinib plus pemetrexed together now and handling it well, and she’s fit in her early 60s.

Devarakonda: Somewhat of a phased approach rather than coming upfront.

Mcgehee: It was just by nature of requirements of insurance.

Devarakonda: What are you doing, Sherry?

Hu: This patient does have a high-risk disease with significant tumor burden and TP53 mutation, so I would discuss with him about [options] No 1, No 3, and No 4, and if he’s up to it, I will give him the combination chemotherapy and osimertinib, but if he's not that motivated, I would probably just give osimertinib. I know No 3 is an option, but I just had 1 patient with a bad adverse effect [AE] with amivantamab. It’s like a blistering wound, not healing. I feel like this AE is even worse than chemotherapy, so I have some reservations about trying it again.

Devarakonda: Carly, what do you think we should do in the clinic to see this patient? You can speak on my behalf.

Irwin: I like [options] 1 and 3. It depends on what the patient wants, and how aggressive they want to be. I think you have to lay eyes on your patients first and have a conversation with them because, yes, some of the toxicities can be pretty challenging for patients, so I think it depends on what they want.

Devarakonda: Bin, what would you do?

Xie: I'll go [option] 4. There’s a high chemotherapy burden plus the central nervous system [CNS] metastasis from the get-go. He’s only 62. I’ll give the most aggressive therapy I can, and I think I’m not afraid of the combination because for patients, a few years ago when we started with osimertinib, when they progress, I don’t take them off osimertinib for CNS protection, and I add it on carboplatin and pemetrexed, and patients generally don’t care for that. It was only 4 cycles. Again, I have felt bitten by osimertinib with AEs, and I have 1 patient who responded beautifully in the lungs. Coughing went away. Everything was better.

Devarakonda: This is on amivantamab?

Xie: Yes, single agent amivantamab. It works beautifully, but she needs direction. She keeps asking the same questions, and we did multiple MRIs, but I can't find anything.

Johnston: This is when I become the old lady in the room. I remember when I was younger watching my more senior partners pivot more towards quality of life than quantity of life, and I find myself doing that more now, and having to actively check myself and make sure I present all options to the patients. I’m a little tired of hurting patients, so I don’t like [option] 3 for that reason. I find carboplatin plus pemetrexed beautifully tolerated, so I would talk to the patient about [options] 1 or 4.

Devarakonda: You brought up something. You said to discuss these options with your patients. If you see a newly diagnosed patient with EGFR, you’re talking about all these options, saying that, look, you have PD-L. I could give you osimertinib, but here you have another option and one more. How do you negotiate that?

Johnston: I would tell them that there are lots of ways to skin the cat, but in my opinion, based on efficacy and toxicities, I would focus on [options] 2. Personally, in this case, I would focus on either osimertinib alone or chemotherapy plus osimertinib. You have to read the room, too. I mean, there are some patients who come in, and they’ve already Googled everything, and they already know all their options, and I’m happy to talk to them about it. I just find that it’s harder for me as I get more [experienced] and know what’s going to happen to them with amivantamab and do it anyway.

Devarakonda: Fair point. Jay?

Lopez: Echoing a lot of the sentiments here, [option] 4 is attractive for the CNS effect of the combination of chemotherapy and osimertinib. This patient has brain metastases, you’d have to consider the burden of disease there. The TP53 mutation does give me some pause about chemotherapy. I’d like to know more about that mutation if there’s any information about it. Osimertinib would be well tolerated. The chemotherapy combination would be more effective with some greater toxicity. As Eileen said, it’s a gentler regimen. I fear amivantamab, having used it. I’d rather assess the patient’s preferences and see how aggressive they want to be and understand their comorbid conditions.

Devarakonda: Overall, it looks like there is still a lot of inertia in trying to move away from the paradigm of using osimertinib as the go-to drug. There are some selective circumstances where you would combine, but the combination is mostly towards chemotherapy plus osimertinib. It looks like that’s what the majority of you are doing.

References

1. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
2. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. News release. FDA. August 19, 2024. Accessed January 15, 2025. https://shorturl.at/HohRl