Afatinib/Osimertinib Treatment Combinations in EGFR-Mutated Advanced NSCLC

The expert panel

As part of a Satellite Sessions program focused on the Cleveland Clinic and surrounding institutions, CancerNetwork hosted a panel discussion on treatment options for patients with EGFR-mutated non–small cell lung cancer (NSCLC). The program was brought together to discuss the use of blood and tissue biopsies in testing for atypical mutations in patients with EGFR-mutated NSCLC. Additionally, treatment options were assessed in treating this patient population, particularly evaluating either afatinib (Gilotrif) or osimertinib (Tagrisso) for atypical mutations.

The panel was led by Afshin Dowlati, MD, associate director for clinical research and professor in the Department of Medicine, Division of Hematology and Oncology at Case Comprehensive Cancer Center. Panelists included Bachar Dergham, MD; Aneel Chowdhary, MD; Adriana Alvarez, MD; and Seema Misbah, MD, hematologic oncologists at the Cleveland Clinic; Melinda Hsu, MD, associate professor of hematology and oncology at University Hospitals Cleveland Medical Center; Giselle Dutcher, MD,medical oncologist at University Hospitals Cleveland Medical Center; and Sharon Zhong, PharmD, thoracic oncology pharmacy specialist at University Hospitals Cleveland Medical Center.

Liquid and Tissue Biopsy Use to Diagnose EGFR-Mutant NSCLC

Dowlati / Is there anyone who is not doing both tissue and liquid [biopsy]? I do not do it for all my patients, but [there are clinicians] who do that in at least 50% of their patients––blood and tissue.

Dergham / I do [a liquid biopsy] when [tissue] is negative, because usually [when] they do the biopsy or laboratory [testing] as a reflex, they run the panel. If everything is negative,
I always order the blood [test].

Dowlati / If the patient comes in and you do not have the next-generation sequencing [NGS] [results] back, and the report says adenocarcinoma—if you do not have your NGS back from your in-house reflex in the clinic, will you send the blood off?

Dergham / Yes, I always do, because it is faster. Sometimes they are going to repeat the biopsy.

Chowdhary / There are [clinicians], especially at Johns Hopkins [Medicine], for example––early on they adopted for every patient doing a liquid and tissue biopsy up front. Again, I do not do that. If I need an answer––the tissue biopsy is still pending, and you want to know because you want to start them [on treatment] in the next week––I will get a liquid biopsy at that time. It is fifty-fifty the way I have done it.

I want to ask in your in-house panel [whether] STK11 and CYP1 [mutations] are included. It is interesting that I did not realize more recently that in our in-house [panel] we have this. It is called a target oncology panel [TOP]. They have not added STK11 and CYP1 to that. We are trying to get it added, that is a big issue. Now, and this I just learned recently, we did not understand that was still in the process of being added. Liquid biopsy is important for us because we are going to miss STK11 and CYP1.

Alvarez / In that particular case, they do the TOP by default if we do not have enough tissue for NGS. The goal is NGS, but if we do not have enough, then we will go to the TOP. I did not know that they did not have [STK11 or CYP1 either].

Chowdhary / They are going to add it on, but that is why I wanted to know [whether] you all have it in your in-house panel.

Dowlati / It is critical in my view. Because patients who are EGFR-mutant positive who have other mutations where you do not have a pure EGFR, you add a TP53, CDK, and NTRK. Those who have other concurrent mutations are the ones who respond [quickly]. There is a short progression-free survival [PFS] with osimertinib. Those are patients who are high-risk, and we will be talking about this. Part of the problem with those panels is you do not get a TP53 [diagnosis] when you do not get other concurrent mutations––you will not have that knowledge. [Melinda], what is your experience there?

Hsu / Absolutely. I trained at Hopkins for my fellowship and the practice was to send liquid and tissue concurrently because we did not have in-house testing at the time. The liquid would come back faster. We are fortunate that we have such a large panel of reflexes with DNA and RNA. I tend to almost always send liquid on any patients who do not have a history of smoking or have a small remote history of smoking just to increase the yield, and potentially consider rechecking at some point in the future. [Circulating tumor] DNA is a bit off-label, but to have that there and to make sure that we are getting all of the data [helps].

Dowlati / Does anyone start treatment before the results
come back?

Hsu / Not unless there is an impending visceral crisis; then I would start with doublet immunotherapy.

Dowlati / When we do not have [results], the best thing to do is a platinum doublet [regimen], but you do not have immunotherapy. When you have no choice, or you do not have enough tissue, you cannot wait. Platinum doublet [therapy] always works.

There is no doubt that the new generation of interventional pulmonologists is more in tune with oncology and ensuring
we get adequate tissue. It is uncommon nowadays to not get adequate [tissue].

If the system does not have that diagnosis of adenocarcinoma on a patient and there is no prior NGS, it is reflex testing. The good thing about our system is they no longer ask about the stage. We do not care what the stage is, we do not even care what the pathology is anymore. If it is coming from the lung and as long as it is not small cell [lung cancer], they will do NGS. They are doing NGS on squamous.

Hsu / Our pathology [department] does not do reflex [testing].
If you ask, there will be pushback.

Osimertinib vs Afatinib Use in NSCLC With Atypical Mutations

Chowdhary / [Afatinib] is an important subcategory drug. I have had a couple of patients who had rare [mutations]. One of them had compound rare EGFR mutations, and he was on afatinib for 4.5 years. When it works, it works well. In this day and age, if you have someone with these rare, atypical mutations, would you go to [oral] osimertinib once a day or even [twice daily], or are you going to go to afatinib?

Dowlati / The bulk of the data for atypical mutations was with afatinib. Then the osimertinib trial looking at atypical [mutations was published] showing a similar response rate. Many clinicians have started using osimertinib for atypical [mutations]. Afatinib is [still] a worthwhile drug to use. One of the things I like about afatinib is the dose range is larger. Osimertinib is [80 mg or 40 mg].
[For afatinib] it is 40 mg, 30 mg, 20 mg, or 10 mg. For some patients, I can find that helpful.

For EGFR mutations discovered during the first line, amivantamab-vmjw [Rybrevant] and lazertinib [Lazcluze] were added. You can now add carboplatin, pemetrexed, and amivantamab as second-line treatment based on the phase 3 MARIPOSA-2 trial [NCT04988295].¹ We have a few patients who received that regimen and are doing well. Then for exon 19 and 21 mutations based on the phase 3 MARIPOSA trial [NCT04487080] we will use a combination of lazertinib and amivantamab.² We will talk about who could potentially be patients who may receive that.

The phase 3 FLAURA trial [NCT02296125] [evaluating] osimertinib in the frontline setting [included patients with] good performance status, classic 19 or 21 alterations, and stable central nervous system [CNS] metastases that were untreated or treated.³ [The study was] stratified based on mutation and race. Over 250 patients were sent to the osimertinib arm, and the other [group] to the standard of care gefitinib [Iressa] or erlotinib [Tarceva]. Gefitinib [was used] mainly in Asia, and erlotinib [was used] mainly in North America and Europe. Until progression, crossover to osimertinib was allowed if the patient on repeat biopsy showed T790M [expression]. That is why, because there was a prior crossover, the primary end point has to be PFS. [Overall survival (OS) was a key secondary end point].

For osimertinib vs first-generation [EGFRtyrosine kinase inhibitors (TKIs)]...there is an 8-month improvement in PFS. The HR was 0.46. If you went to OS, it had a statistical survival benefit. The P value was borderline there. There was a survival benefit of about 7 months. The main thing was the PFS curves were a lot better than the OS data. [It was] no doubt a much better-tolerated regimen when you gave osimertinib. We all have experienced osimertinib as substantially improving the quality of life of our patients without those classic severe adverse effects and diarrhea. We still get them, but not as severe.

Then, they also most recently looked at the brain metastases and updated some of the data. If you look at the PFS in those with CNS metastasis and the PFS in those without CNS metastasis, you can see there was a 9-month improvement without CNS. A 6-month improvement in those with CNS metastases [was observed]. The HRs were about the same. In other words, osimertinib works with or without brain metastases in patients.

[Osimertinib] became our standard of care based on the FLAURA trial. So then came the phase 3 FLAURA2 trial [NCT04035486], which took the best player, osimertinib alone, and randomly assigned patients to 80-mg osimertinib.⁴ Again, a large trial of 550 patients to chemotherapy plus osimertinib, carboplatin, or cisplatin plus pemetrexed. Then after 4 cycles of platinum pemetrexed, they continued to osimertinib and pemetrexed. What is the downside to this?

When we give [osimertinib] to the patient, they [check in] every few months when they are doing well. [In the randomized study], what happens is that every 3 weeks they have to come in still for their pemetrexed long term. It is a lot more involved for the patient than giving osimertinib alone and then stratified by race, the type of EGFR mutation, local or essential testing, and performance status.

They looked at the primary end point, again PFS, in these settings with secondary end points of response rate and OS. This trial met its end point where [osimertinib plus chemotherapy] was superior to [osimertinib monotherapy]. The FDA approved this year the combination of chemotherapy and osimertinib because it is better than osimertinib [alone].⁵ Who has given chemotherapy plus osimertinib in their practice?

Chowdhary / [I treated] one patient. Not like [the one outlined in] FLAURA2, though. I still have not done the FLAURA2 [regimen]. We had a [male patient]––it was interesting. FLAURA2 had been approved and he had a large aortopulmonary window node...but that was the only node he had.... He is middle-aged––61 or 62 [years]––but quite fit. We know that immunotherapy does not work right in the neoadjuvant setting and the whole plan was to give him chemotherapy, maybe immunotherapy in that neoadjuvant setting.

I brought him in and I said “FLAURA2 is out. It is not going to be indicated. What if I gave him chemotherapy plus osimertinib, because he had EGFR exon 19 [mutation]?” They said sure, and insurance let it fly. He had a fantastic response. He got the
4 FLAURA2 cycles in the neoadjuvant setting and a great response [occurred].

Dowlati / I heard that 1 or 2 of you have used the FLAURA2 regimen. I have used it on one patient in March 2024. Why have you not used it? Let us start off with that. Why have you not used FLAURA2 if it improved survival?

Dutcher/ My main thing is patient factors. [Patients], especially an older patient population, are not keen on getting chemotherapy. When you give them the option of [taking] a pill every day and [seeing] me once a month or once every 3 months, vs [coming] in every 3 weeks, the choice is clear.

Dowlati / What if I told you that patients have more than a 50% chance [of recurrence] in the first 10 months? It is a bad actor. What would you do then?

Dutcher / I have some regrets that I should have pushed chemotherapy a little harder in patients who I did not think would die in 6 months and they died in 6 months. They [likely] had some clinical brain metastases or rapidly progressed. I am earlier
in my career, so I do not have as good a feel for these people
until I see a couple. [Then you say,] “OK, I do not want this to
happen again.”

Dowlati / The point of this is intensification. Up-front intensification will improve survival despite subsequent therapy decisions. Ultimately, up-front intensification is important for some patients.

Zhong / If I had a young patient with CNS metastases and [who was] a candidate for this, I would consider [osimertinib with chemotherapy]. I have not had that opportunity.

Misbah / Even for the younger, more fit patient you did give this regimen to, it can be a hard sell for a patient to come in every 3 weeks when they want to maintain their quality of life. In terms of pemetrexed maintenance, it is interesting because, on average, patients [received] about 12 cycles of pemetrexed maintenance. [Patients did not receive] much of the pemetrexed maintenance, but we still see this sustained separation of the curves.

Chowdhary / I was going to add that I completely agree with Giselle...I have 6 or 7 patients on osimertinib right now. They are all between the ages of 77 and 88. That is the issue right now. Especially on the east side [of Cleveland], you have a more elderly population. I think it is case by case.

I agree if it is a young patient with a huge burden of disease. Again, if I get another patient with EGFR-positive [mutations who] need neoadjuvant therapy, I know we are still waiting for the osimertinib data in the neoadjuvant setting, and [they are] likely going to be impactful. If someone is young, or has high [-risk] disease, especially with a lot of brain metastases, [or if they are] symptomatic as well, these are cases where I use it. One thing I am impressed by is the CNS [data] because I was not expecting that. If you look at the numbers from FLAURA and FLAURA2, osimertinib is doing exactly as it did before.

[Osimertinib] is consistent, which was interesting because it is not a trial effect or a patient population effect. When you look at the blinded independent committee review on PFS and OS, they are exactly a reflection of the FLAURA trial. Why the CNS was better when you have metastases, I do not know. Conventional wisdom is that chemotherapy is not crossing the blood-brain barrier unless osimertinib is enacting some changes within that medium where chemotherapy is having an effect. That is the only thing you can think about. Osimertinib vs osimertinib with chemotherapy added, it is giving you a better CNS benefit.

Alvarez / You cannot have it all.... The presentation of patients with EGFR is sometimes atypical. I have healthy-looking patients who did not even know they had cancer or bone metastases. Should I intensify [treatment for] these patients? They have a lung nodule and then multiple bone metastases. How much effect am I going to have with the chemotherapy? I have a patient with CNS, a more visceral disease. [It is likely] going to be more aggressive.

Dowlati / I think the key is to understand who would benefit from more aggressive [therapy].

Alvarez / I do not see it, not for everybody.

References

1. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.Annal Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117
2. Cho BC, Felip E, Spira AI, et al. LBA14 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. Annal Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41-50. doi:10.1056/NEJMoa1913662
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 20, 2024. Accessed November 5, 2024. https://shorturl.at/3mLOd