Roundtable Discussion: Neal Discusses Molecular Testing and Treatment for EGFR Exon 20+ Lung Cancer

Joel W. Neal, MD, PhD

KRIJANOVSKI: We usually do FoundationOne testing [of] PD-L1 expression for patients with treatment-naïve, stage IV cancer. If the patient is symptomatic, we do Guardant360 [testing].

Sometimes the Guardant360 results come back without any targetable mutations; [in that case], I might give a cycle of chemotherapy without immunotherapy [while I] wait for the FoundationOne [result] to come back. That has happened on a couple of occasions. I am from Sutter [Medical Foundation] in Northern California. I am in a group [that] sees garden-variety patients, [of whom] 20% to 30% [have] lung cancer.

Most of the patients are older. Rarely do we get young people or Asian nonsmokers, but [sometimes] we do. We check mostly non–small cell lung cancer for targetable mutations. We will start with the targeted agents, if available, and we will do Guardant360 [testing] and FoundationOne PD-L1 expression [testing]. For patients who do not have any targetable mutations, we sometimes do 4-agent regimens. I have given carboplatin and paclitaxel [Taxol] plus bevacizumab [Avastin] to 1 patient with a good response.

NEAL: I have heard that if you suspect 1 of these driver alterations in somebody who [has never smoked], you can give the chemotherapy without the immunotherapy while you are waiting for the NGS results, which can take 2 or 3 weeks. [Dr Chaudhary,] what do you do at Pomona Valley Hospital in Southern California?

CHAUDHARY: I think we are getting NGS in all our newly diagnosed patients with stage IV cancer. I recently saw a very symptomatic patient in the inpatient setting. I just ordered EGFR [testing]. She is Asian and a nonsmoker. If I need results fast, I [test for only those alterations that I suspect, such as EGFR and ALK]. If I have a patient who is not that symptomatic, I will wait for the results of NGS. Sometimes I just give chemotherapy to a sick patient in the inpatient setting. I do not wait for the results and then tailor treatment based on whatever actionable mutation comes in.

NEAL: Not to favor branding, but what is the platform of reference for you?

CHAUDHARY: We use FoundationOne and Guardant360. It depends on the patient’s insurance. Sometimes we use Quest [Diagnostics].

AGARWAL: I just moved to Polyclinic, in Seattle, 3 months ago. For us, the pathologist group does reflex [testing] to the common array of 6, which includes PD-L1, EGFR, ALK, ROS1, KRAS, and NTRK. If I need anything beyond that, then [we use] the FoundationOne panel. I have not used the liquid biopsy on any patient.

NEAL: They have a polypanel for most of the actionable biomarkers, but now that we are up to 9 actionable drivers, some may or may not be covered. What about RET, for example?

AGARWAL: RET is not part of the panels so far.

NEAL: But if you order the reflex NGS or you order NGS on your own, then you will hopefully see RET.

MIEL: [I am from The Oncology Institute in Corona Del Mar, which is in] Orange County, California. I go to 2 clinics: Fountain Valley and Santa Ana. Our group has a lot of capitated contracts. That is one of the challenges [I face]. I automatically order NGS for patients with stage IV cancer, but sometimes I am limited by [the contract]. Now, on occasion, you will have patients whose initial biopsies are insufficient for testing. I do liquid biopsy for those patients, and my preferred [platform] is Guardant.

For patients whose cancer is stage IB though IIIA, I just order PD-L1 and EGFR [testing] since we need those for adjuvant treatment. I am having a hard time getting NGS for those patients; I get pushback from payers. So for those patients I just order the [tests] that I think will be helpful in the adjuvant setting.

NEAL: I think that the payer pressure is something that is felt differently by different institutions. At Stanford, for example, we tend to accept new patients selectively, so I think we have less payer pressure.

HARRIS: I am [at MultiCare in University Place, Washington,] very close to Seattle. We did have recruitment to send NGS to the University of Washington for a while. That was a couple of years ago, with multiplex testing, but it took about 6 weeks to get the results back, so I think we stopped using them as much. I tend to do the same as Dr Miel, ordering a FoundationOne [test]. I am a little confused as to the accuracy of [the results for] MET exon 14 skipping mutations and whether [they] can be reliably [detected] with [anything] short of RNA testing. I know [MET exon 14 skipping mutations] are not frequently seen, maybe in the range of 1% to 2%. I also do not know what to do with KRAS mutations [though] I think there is at least 1 [KRAS-targeting] drug available for second-or third-line treatment, I have never seen a KRAS mutation, even though I check for it.

NEAL: The KRAS [question] is a little easier to [answer]. KRAS [mutations] should be seen fairly frequently. The KRAS G12C mutation is the actionable mutation. The C is for the cysteine residue where these irreversible inhibitors bind. Sotorasib [Lumakras] and adagrasib, which is not yet approved, both [target this mutation, which is observed in] 13% [of all patients with lung cancer, regardless of smoking status]. That is about the same as the percentage represented by EGFR-mutated lung cancer among smokers. So the KRAS [mutation] is worth checking for. All the NGS panels cover it well.

By now, most NGS should cover the MET exon 14 splicing mutations pretty well. Originally, those intronic regions of MET were not sequenced, so [those mutations were] missed, but FoundationOne and almost any other NGS panel should pick up 90% to 95% of those mutations. The frequency of [those] MET mutations in both smokers and never-smokers is probably 3%, about as frequent as ALK mutations. These MET mutations are definitely worth looking for, and now we have 2 FDA-approved MET-targeting drugs: capmatinib [Tabrecta] and tepotinib [Tepmetko].

DNA NGS detects [these MET mutations] most of the time, but RNA is going to be the most sensitive test for finding the large rearrangements as well as the MET splice mutations. At Stanford, we developed in-house NGS as a blood-based assay and then [applied] it to tissue. Our people say we might miss a couple of MET exon 14 [splicing mutations], so when I find [no mutations] in a tumor specimen, I will do RNA analysis on it. We do in-house RNA analysis, but we do not do it [as a reflex].

But if you find another driver mutation in KRAS, EGFR, or something else, you do not need to keep looking. You can believe positive results from liquid [biopsy], but if the results are negative, you have to go to tissue. If your results from tissue are negative, keep looking. There are a few patients who have no actionable driver mutation, just a mix of random mutations in KEAP1, STK11, and other [assorted] genes. If you find [a mutation in] 1 of the 9 actionable drivers, you are done. If you do not, it is worth looking at the next level, especially in never-smokers.

RASILA: [At Sutter Health, in Danville, California] all my stage IV patients automatically get PD-L1 and FoundationOne NGS testing. I am not a big fan of liquid biopsy; I always try to get a repeat [tissue] biopsy if it is possible, but I will have FoundationOne reflex to a liquid biopsy if there is not enough tissue. I have not had good luck with liquid biopsies. I have never found anything actionable on the liquid biopsy, but when I have done a repeat tissue biopsy, I have sometimes been able to find mutations, so I always try to get tissue.

NEAL: Yes, I think tissue is the gold standard, but even tissue can fail sometimes, and there can be limitations, especially with bone biopsies—decalcified bone biopsies or small specimens.

EY: I practice at [Oregon Health and Science University Knight Cancer Institute], and we do NGS in house. I share the concern raised by others that it takes a while to get results; our wait time is 2 weeks if we are lucky. The PD-L1 testing is done separately and those results always seem to come back first. I am pretty enamored with Guardant liquid biopsy because the turnaround [time] is good and my scientific colleagues tell me that it is pretty reliable. In fact, [I had a case in which] an EGFR exon 19 mutation was picked up [by Guardant liquid biopsy] on [a patient whose cancer] was going to be hard to biopsy. I do not hesitate to use the Guardant blood biopsy if I cannot get good tissue safely, and it is faster.

NEAL: What turnaround times do you see with the liquid biopsies?

EY: Five days, every time.

NEAL: I see 5 to 7 business days. It depends on the shipping and things like that. It is undeniable how much faster it is to get a tube of blood from a patient than a block out from pathology. That is impressive.

EY: The turnaround time is very [beneficial] in this setting. In a patient who has to have treatment [immediately], I [would] potentially give a cycle of chemotherapy, but I have not faced that too often.

NEAL: I think it is fast, and you can believe a positive [result], but when [the result] is negative, you cannot [depend] on it and start immunotherapy [especially, for example], in a never-smoking woman.

FANG: I am from Stockton [Hematology Oncology Medical Group] in California. I test all comers when they have stage IV disease. We [currently] test all comers with early-stage disease [as well] because we are participating in a trial [LIBRETTO-432; NCT04819100] wherein all comers are tested for RET fusion to [assess the efficacy of selpercatinib (Retevmo) as] adjuvant treatment.

Usually, we use FoundationOne. PD-L1 testing is typically done [for all patients] in house, so that result will come back first. [This can be challenging] because, as you probably know, sometimes a patient has very high PD-L1 levels, and you want to treat the patient, but the genomic study results are not back yet. I have used liquid biopsy before, frequently with Guardant, and in 2 of my patients, EGFR mutations were detected by Guardant first. My experience with Guardant is quite good. In the past, 4 or 5 years ago, we did less panel testing. I have been using a big panel since 2018, and I have not had any problem with the payer so far.

NEAL: Yes, it is interesting that FoundationOne now offers liquid biopsy testing, but everybody is still using FoundationOne just for tissue and [using] Guardant for liquid. Guardant is fast, also.

LI: I work out of Providence Mission Hospital, Mission Viejo, California. Our protocol has changed recently. We do not have a completely standardized protocol. I used to use in-house testing; NeoGenomics is nearby, but I found the turnaround was slow. I also use Guardant. I have had good success with Guardant because of the fast turnaround. Even with inpatients, I have been able to identify actionable mutations and even start treatment with an EGFR inhibitor such as osimertinib [Tagrisso] and a few others. I also try to wait, since there is such a quick turnaround, and inpatients are usually not great candidates for chemotherapy. In terms of NGS testing, I like Caris, and I have used FoundationOne in training, but I am just more comfortable with Caris. We worked it out so that all we have to do is contact our pathology department and [ask them to] run the Caris panel, and they will run it. In most cases, I will use both Guardant for speed and tissue NGS for the full panel.

ZHOU: [At Gould Medical Group in Modesto, California,] I use FoundationOne for gene sequencing and also for PD-L1 testing. I normally wait; if there is not enough tissue, then I order liquid biopsy. I know some of my colleagues here order the 2 tests at the same time, but I tend to wait.

RIESS: I have been sending both. I usually send plasma to Guardant for the same reason everybody else does. It is a quick turnaround time, and then we do reflex in-house PD-L1 testing, but I usually send that out to FoundationOne. If I do not get a good result, and if the patient is a never-smoker and so forth, I will often send for RNA-based testing. That is usually what I do, and I have been generally pleased with the results. It is nice to have something back quickly with Guardant.

NEAL: For me, it depends on how quickly I think I am going to get my tissue testing results back. The Stanford pathologists will reflex anything, even early-stage disease, to in-house PD-L1 testing. We still have our old rapid EGFR tissue test, and the results of that are back within a week. We do fluorescence in situ hybridization to assay ALK and ROS in the tissue, which is kind of archaic, and we have in-house NGS and RNA-based testing.

Our in-house NGS takes approximately 3 weeks, which is a little long, but it has come down from 5 weeks. The more we order, the faster it comes back. For send-outs, I will usually use either Guardant or FoundationOne. I think everybody here is doing comprehensive molecular testing, and if there is no other message, it is this: Do not miss a patient with an actionable driver mutation. There are some drugs that work spectacularly well, but if you miss these patients, they will lose the opportunity to get a big boost in [survival] time.

FANG: I just had 1 patient who was on amivantamab [Rybrevant] and has since now switched to mobocertinib. When she was on a full dose of 160 mg, she became quite sick with diarrhea and other adverse events [AEs]. She quickly decreased the dosage [on her own] to 80 mg and she tolerated that very well and had no AEs whatsoever. She stayed on that dosage for 3 or 4 months, and we did a PET scan on her and [saw that the disease had] responded. I then encouraged her to increase the dosage to at least 120 mg, but she preferred to stay on 80 mg. So far, in my experience, [mobocertinib] is better tolerated than amivantamab.

NEAL: What were the [challenging] AEs with mobocertinib?

FANG: When the patient was started on 160 mg, she had very bad diarrhea. She very quickly decreased [to 80 mg]. When she came back, she said that the diarrhea was much better, so she stayed [at that dosage]. The diarrhea was the main AE and dry skin was [also] an issue. Neck swelling, which was bothering her a lot when she was on amivantamab, [was not a problem with mobocertinib].

NEAL: I have a fair amount of experience [in the context of] the phase 1/2 trial [NCT02716116], [and now] a phase 3 clinical trial [NCT04129502] that examines mobocertinib vs chemotherapy in the frontline setting. I have probably treated a dozen or more patients with this drug. The diarrhea, for some patients, can be tough. Some patients tolerate the full dose just fine, but I don’t know why.

The skin effects, rash, and paronychia can be a little harder to tolerate. Most people have decreased appetite, which we see with many tyrosine kinase inhibitors [TKIs]. I have not seen very much corrected QT interval prolongation. I will see [the interval slightly exceed] 500 ms on an EKG, but I don’t worry too much. I have not seen cardiomyopathy, and we have occasionally had a patient with interstitial lung disease or pneumonitis.

My management guidelines for mobocertinib [are similar to what] I do for osimertinib. I think [mobocertinib] is a little tougher [to manage] than osimertinib. [I think that] mobocertinib is akin to afatinib [Gilotrif] and dacomitinib [Vizimpro] with respect to the skin [AEs] and the diarrhea, but I think the diarrhea can be manageable with loperamide [Imodium] and similar agents. The data seemed to show that patients who dose-reduced did not do quite as well, so I prefer the 160-mg dosage and maybe [reduce it to 120 mg] if I have to, but I think that 80 mg is a little [too] low. I would certainly encourage the patient to get back up to 120 mg, if possible, and manage the diarrhea.

HARRIS: How bad is the nausea with this drug?

NEAL: The nausea is not unmanageable. This drug mostly [affects the] lower gastrointestinal [tract]. I have occasionally had patients with nausea. I usually manage it with prochlorperazine [Compazine] or similar drugs, as opposed to ondansetron [Zofran], which is associated with QTc prolongation. But a little bit of prochlorperazine is fine; [you can use] ondansetron, if you need to, and just monitor the EKGs periodically. With osimertinib, I have seen QTc prolongation that was clinically significant, and I could not continue the drug. I have seen cardiomyopathy in a few patients, and I have seen pneumonitis in many patients. I think [that with respect to these] special considerations, mobocertinib may be better than osimertinib, but the diarrhea and the rash [that are associated with mobocertinib] are [similar to those of] first-generation EGFR TKIs.

The increased blood creatinine [level] is interesting, and we have not fully [explored] this yet, but I think it is an artifact of the drug. Many of our patients have the creatinine go up, and then when they stop the drug, [their creatinine level] will go back down. The cystatin C test [results are] normal, which means the creatinine clearance is artificially high because the drug is impairing creatinine excretion, but the cystatin C is fine. In my experience, this drug is tolerated well enough, but you do have to encourage people to get through the diarrhea and the rash. We have supportive dermatologists who are happy to see our patients.

ZHOU: I found it interesting that both [amivantamab and mobocertinib were approved by the FDA] at the same time,^1,2 but the overall response rate for amivantamab was higher than that of mobocertinib, approximately 40% vs 30%, respectively [From the Data^3,4]. However, I can appreciate that the median duration of response [was longer for mobocertinib [17.5 months (95% CI, 7.4-20.3)⁴ vs 11.1 months for amivantamab (95% CI, 6.9-not reached)³]. Also, mobocertinib is more convenient orally [vs intravenous amivantamab]. I do not know if you have a preference for one vs the other, but it sounds like mobocertinib might be the first choice.

NEAL: I think 1 of the hardest questions is which [of these 2 drugs] we should use first. They should work [when used consecutively], so that is another consideration.

AGARWAL: I just started someone on [amivantamab] about a month ago. [They have had] 2 infusions so far. I have not seen the rash yet and the infusion reaction was nothing more than [what is usually seen] in the infusion room. So far, so good.

FANG: My impression of this drug is that the edema is profound. Also, my patient’s albumin dropped to a very low level very quickly. She [had a] normal albumin level, and [it dropped to] 2.7 g/dL after infusion. I think that is the reason for her edema, and we tried the furosemide [Lasix], but nothing helped her edema. Eventually, she could not tolerate the drug. I feel like [bispecific antibodies] should be better tolerated than chemotherapy.

NEAL: For whatever reason, all the MET inhibitors, even the MET-inhibitor TKIs, cause a lot of peripheral edema. Even our old-but-good drug crizotinib [Xalkori] caused a lot of edema, because it inhibited ALK, ROS1, and MET together. That MET inhibitor–related edema can be pretty tenacious and not usually responsive to furosemide. Some patients get horrible edema, but they cannot tolerate it, and some do not have it at all. It is variable. When I talk to patients, I often [discuss the AEs] in the context of the clinical trial, so [that the patients] see all [of the possible AEs]. They ask me, “Am I going to get all of these?” I tell them, “No, probably just 2 or 3 that will bother you. But I cannot tell you which 2 or 3 until we start the drug.” Every [patient] is slightly different.

[This drug has an unusual dosing schedule] and the infusion-related reactions [almost always happen on the first day of treatment]. You give one-third of the regular dose as a test dose on the first day. You give two-thirds of the regular dose on the second day. A week later you begin giving [weekly doses, which continue for the rest of the month], and then it goes to every other week after that.⁵ So the infusions are fairly frequent, even when the schedule stabilizes after the first month. Some patients may have an infusion-related reaction on the second day, but it seems to be that once that [small initial] dose [has been given], patients do not react anymore. This follows a pattern similar to what is observed with rituximab [Rituxan].

FANG: Have you tried using albumin for the management of edema? The albumin [level] of my patient [went] down to 2.7 g/dL, so I was just wondering [about] offering her an albumin infusion.

NEAL: At least from my inpatient experience, albumin lasts [for such a short] time that you cannot give people infusions fast enough to make a difference. And this sort of edema is persistent over months; I do not think [a patient] would want to come every 6 hours for their albumin.

FANG: That is a good point.

NEAL: I do not have any good solutions for the peripheral edema. Maybe dose reduction and extension of treatment would work if a patient is doing well.

HARRIS: Is the rash treated topically or you need to use corticosteroids?

NEAL: I think [the rash is managed in] the same manner as are the usual EGFR[-inhibitor] rashes: topical corticosteroids or, if you think it is more of a pustular and bacterial rash, topical or [oral] antibiotics. My old favorite was doxycycline [Monodox], but I feel like that causes too much stomach upset, so now I generally give 500 mg of cephalexin twice a day, and that seems to take care of most rashes.

Emollients, also, [are important]. I hand patients a sheet of paper [with a list of things like] Aquaphor and CeraVe. I tell them to [try different moisturizers and] see which one they like the feel of on their face, chest, and back, and I tell them to use it twice a day. [I suggest that they] have somebody [help them apply it]. Patients should do it after every bath at the very least, preferably twice a day. Moisturizing is the first barrier of defense.

A lot of research has shown that EGFR inhibitors open up holes [between] the epithelial cells, so it is like your castle wall has holes in the mortar between the bricks, and then bacteria invade. So it is not only a dryness problem. The barrier moisturizers are the first line [of defense], and then antibiotics [can be helpful, too]. Clindamycin lotion is effective. Fluocinolone oil can be good for the scalp, and then there are also the [oral] antibiotics. Most patients get along well with a combination of these.

_REFERENCES:

_{1. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed August 29, 2022. https://bit. ly/3cKcYkX}

_{2. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. September 15, 2021. Updated September 16, 2021. Accessed August 29, 2022. https://bit.ly/3TDa9CF}

_{3. 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}

_{4. 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}

_{5. Rybrevant. Prescribing information. Janssen; 2021. Accessed August 29, 2022. https://bit.ly/3TAlweP}