Amivantamab vs Mobocertinib in Exon 20 NSCLC

Meet the experts.

An expert panel of lung cancer specialists convened for a Frontline Forum focused on testing, treatment options, and the management of patients with EGFR exon 20 non–small cell lung cancer (NSCLC). The panel also addressed a variety of other subjects, including the continuum of care and efficacy results from relevant trials.

Alexander I. Spira, MD, PhD, FACP, codirector of the Virginia Cancer Specialists Research Institute and director of the Thoracic and Phase I Program, led the discussion. He was joined by Christine Bestvina, MD, assistant professor of medicine, University of Chicago Medicine; Joshua K. Sabari, MD, assistant professor of medicine and director of high-reliability organization initiatives, Perlmutter Cancer Center; Millie Das, MD, clinical associate professor of medicine and oncology, Stanford Health; and Misako Nagasaka, MD, PhD, associate clinical professor, University of California, Irvine.

Testing for NSCLC Gene Mutations

The panel began with a review of genes and mutation types commonly associated with NSCLC. Sabari noted that about 1% of his patients have squamous disease compared with about 20% who present with adenocarcinoma; he treats both aggressively. Testing is required to determine if patients harbor specific mutations. Bestvina has recently changed her practice from testing only nonsmokers who present with squamous disease to testing everyone. Nagasaka tests all patients with squamous and nonsquamous disease alike and has started testing patients with early-stage disease.

Das said she works with pathology to test all patients who present in the clinic. “I’ve been trying to push our pathologists to perform reflexive testing on any lung cancer specimen, regardless of stage or histology. By the time these patients show up in our clinics, hopefully, we have the data that we need. As has been said before, we do sometimes see some driver alterations in patients with squamous cell carcinoma and I’m always glad that I tested that patient.”

Whether to test a patient is often debated. While clinicians increasingly test every patient they see, some still prefer to wait and be more selective. Spira noted that those in the breast cancer community, who commonly see mutation in the disease they treat, never discuss whether to test; they test automatically.

The panel also spoke about the use of tumor tissue vs plasma and liquid biopsy. Spira wanted to know if, in practice, his colleagues obtained comparable results regardless of test type. Nagasaka recommends using both, especially for patients with stage IV disease.

Bestvina cited a poster she presented at the 2023 American Society of Clinical Oncology Annual Meeting comparing the use of next-generation sequencing (NGS) to PCR testing.¹ NGS was more cost-effective based on the accuracy of the diagnosis and a fast return on the results. In terms of when to test, results are typically presented to a tumor board and a workflow has been established to include testing for EGFR mutations.

For Nagasaka, these tests are not done reflexively and need to be ordered. For Sabari, testing for EGFR and ALK mutations is done reflexively, but is based on patient’s immunohistochemistry (IHC). “[Using IHC] misses a ton of the EGFR mutations. For ALK [testing it] gets a little bit more sensitive. Then for NGS, we tried to order tests reflexively, but there are reimbursement issues, particularly if someone’s had testing done before, whereas if you’re early stage, some insurance companies won’t cover anything outside EGFR [testing] because that’s where the therapies are approved,” said Sabari.

Spira questioned the use of IHC results to determine the need for EGFR or ALK testing. Sabari said these results are returned within 24 to 48 hours and can help better inform decisions.

The big question revolves around why all institutions, from community to academic practices, don’t reflexively test in the lung cancer space. Nagasaka said it comes back to reimbursement issues. Specifically, the pathologists conducting these studies do not have relationships with these patients and are typically not oncology-specific, but service the entire institution.

CHRYSALIS Trial

The panel looked to the results of the phase 2 CHRYSALIS trial (NCT02609776) which evaluated amivantamab (Rybrevant) in patients with EGFR exon 20 insertion–mutated NSCLC who have progressed on
platinum therapy.² A total of 258 patients were given the recommended phase 2 dose of 1050 mg of amivantamab once weekly for the first 4 weeks and then once every 2 weeks beginning at week 5.

Patients had a median age of 62 years, 59% of patients were women, 49% were Asian, and all had received previous platinum-based chemotherapy. Patients had received a median of 2 prior lines of therapy, with 25% receiving previous EGFR tyrosine kinase inhibitors and 46% having received previous immune-oncology therapies.

The objective response rate (ORR) was 40% (95% CI, 29%-51%). The duration of response (DOR) was 11.1 months (95% CI, 6.9-not reached [NR]) and 75% of responses were observed at the first disease assessment. The clinical benefit rate was 74% (95% CI, 63%-83%), which included an additional 28 patients who had stable disease at 11 weeks or more.

All 81 patients in the efficacy population had circulating tumor DNA (ctDNA) or tumor samples submitted for testing, and 63 patients had detectable ctDNA. If patients harbored mutations, antitumor responses were observed. When NGS testing was conducted, 1 patient had MET amplification with a partial response.

Overall, 58% of patients died. The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5-10.9). The median overall survival (OS) was 22.3 months (95% CI, 14.6-NR), and 23 deaths occurred, although results for this remain immature.

In terms of safety, the median duration of treatment was 3.7 months for this population. In patients who had EGFR inhibition, adverse effects (AEs) associated with it were rash (86%), paronychia (45%), stomatitis (21%), pruritus (17%), and diarrhea (12%). AEs associated with MET inhibition included hypoalbuminemia (27%) and peripheral edema (18%). Additionally, 4% of patients had interstitial lung disease.

In 35% of patients, grade 3 or higher AEs occurred. The most common was hypokalemia (5%), and 4% of patients each experienced rash, pulmonary embolism, diarrhea, and neutropenia. Grade 3 or higher treatment-related AEs occurred in 16% of patients, and 30% experienced serious AEs.

Dose reductions related to treatment occurred in 13% of patients, and 4% had treatment-related discontinuation. There were no grade 5 AEs.

After the results were discussed, the panelists were asked how they felt about these data and if it would begin to change their standard of practice. “I did feel that the data were strong enough for me to consider using this in the second-line [setting]. Now the field has to move on to figuring out how best to manage to treat these patients, including the management of AEs,” said Nagasaka.

Das said she is excited to be able to use this treatment in the second line, as TKIs cannot be used up front in this patient population. Sabari said this trial was practice-changing for his clinic, but he wonders how best to implement this strategy in the first-line setting.

Clinical Study of Mobocertinib

A phase 1/2 dose expansion/escalation trial (NCT02716116) evaluated mobocertinib (Exkivity) at 160 mg daily in patients with EGFR exon 20 metastatic NSCLC, assigned to either the platinum-pretreated patients (PPP) cohort (n = 114) or the EXCLAIM cohort (n = 96).3 Demographics between both cohorts were similar.

In the PPP and EXCLAIM cohorts, 35% and 34% of patients had brain metastases, respectively. In the PPP cohort, 23% of patients remained on treatment vs 26% in the EXCLAIM cohort, the median time on treatment was 7.4 months vs 6.8 months, and the median follow-up was 14.2 months and 13.0 months.

In the PPP cohort, the ORR was 28% (95% CI, 20%-37%) by independent-
review committee (IRC) assessment and 35% (95% CI, 26%-45%) by investigator assessment. Per IRC, the confirmed disease rate was 78% (95% CI, 69%-85%). The median time to IRC-assessed confirmed response was 1.9 months (95% CI, 1.8-3.6) and the median DOR was 17.5 months (95% CI, 7.4-20.3). The median PFS was 7.3 months (95% CI, 5.5-9.2) and the median investigator-assessed PFS was 7.3 months (95% CI, 5.6-8.8). The median OS was 24.0 months (95% CI, 14.6-28.8).

In the EXCLAIM cohort, the ORR by IRC was 25% (95% CI, 17%-35%) vs 32% (95% CI, 23%-43%) by investigators. The median time to IRC confirmed response was 1.9 months (95% CI, 1.8-3.6) and the median DOR was not estimable. Disease progression occurred in 55% of patients, the median PFS was 7.3 months (95% CI, 5.5-9.1), and the median OS was not reached. The brain was the first site of investigator-assessed progression in 38% of patients, and 68% had progressive disease.

The most common treatment-related AEs in both cohorts were diarrhea and rash. Diarrhea was reported as a grade 3 AE in 10% or more of patients.

When to Sequence Amivantamab vs Mobocertinib

Spira pondered what the treatment options would be for patients during or after second-line therapy and whether a biopsy was taken again. Nagasaka will typically conduct a biopsy, but after using amivantamab or even mobocertinib, there are not many options outside a clinical trial.

Das discussed the use of single-agent chemotherapy like gemcitabine or docetaxel as an interlude between the 2 drugs. She will begin with amivantamab, proceed with chemotherapy, and, if disease progression occurs, she proceeds with mobocertinib.

Nagasaka prefers to use amivantamab based on the ORR; however, she still has a conversation with her patients to discuss the treatment.

“Amivantamab is a great drug, but it’s inconvenient. You have to be in the clinic for the first 2 days consecutively, then every week for the first 5 weeks, and then every 2 weeks thereafter. Some of our patients don’t have the luxury of back-and-forth transportation.”

Mobocertinib, an oral agent, can be more convenient. Das, who practices in both an academic and a community setting, still prefers amivantamab over mobocertinib because of the toxicity profiles observed.

The conversation then turned to the toxicity profiles of the 2 drugs. In the CHRYSALIS study, patients typically experienced flushing 35 to 45 minutes into the infusion. When this occurs, Sabari stops the drug for the day and will continue the rest of the treatment the next day.

Regarding mobocertinib, diarrhea is a concerning AE. As this is an agent that is given to patients who cannot travel back and forth to the treatment centers, Sabari likes to set up a plan of action on how to best manage this AE if it occurs.

Grade 2 diarrhea has been defined as 7 bowel movements a day. In a trial where the median duration of treatment was 15 months, this AE can take a
serious toll on patients and their quality of life.4 Sabari noted that diarrhea can be managed but clinicians need to be “hyperaware” when it occurs. Another option is to dose-reduce or hold the drug, but that could impair the efficacy of the treatment.

“The real thing is having a patient understand that the pill is not easier than the intravenous [treatment]. It might be easier to [stay at home] and time [won't be spent] in the cancer center, but it’s not easier from a tolerability standpoint. With the efficacy data we reported, amivantamab has a slightly higher edge. As we said, there’s a lot of work to be done in this space. We’re not where we want to be,” said Sabari.

Bestvina pointed out that these patients have received prior chemotherapy, so it is often already part of their routine to come into the treatment facility.

The Next Steps

Spira noted how quickly new drugs can come onto the market: “Who would have thought 10 years ago that we were going to have 2 drugs being developed for EGFR exon 20 insertions? It is mind-boggling if you think about it.”

One unmet need that Bestvina hopes these new drugs in the pipeline can help address is central nervous system (CNS) efficacy. Spira agreed, calling it a big concern in this space. When patients present with brain metastases, clinicians often want to avoid whole-brain radiation. When Das sees patients presented with brain metastases, she refers them to CyberKnife, a fully robotic radiotherapy device.

Sabari uses stereotactic radiotherapy and has experience with investigational drugs like CLN-081, which has a cleaner toxicity profile, and BLU-451, which addresses CNS efficacy.

A big concern with the development of these new drugs is toxicity: Will they be cleaner than amivantamab? Will they affect the gastrointestinal system more severely than mobocertinib? Sabari hypothesizes that the drugs in development could be combined with amivantamab to create better
opportunities CNS-wise.

References

1. Bestvina CM, Waters D, Morrison L, et al. Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction (PCR) versus next-generation sequencing (NGS) testing strategies in metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol. 2023;41(suppl 16):6638. doi:10.1200/JCO.2023.41.16_suppl.6638
2. 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
3. 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
4. MedGen: Common Terminology Criteria for Adverse Effects. National Library of Medicine. Accessed July 17, 2023. bit.ly/3PWTJ91