Newer Targets in NSCLC Lead to Directed Therapies

New approached and novel agents are constantly being developed to identify and treat emerging targets in non– small cell lung cancer (NSCLC).

EGFR Exon 20 Insertion Mutations

EGFR exon 20 insertions are not among the more common and easier to treat EGFR mutations in NSCLC, such as EGFR.

Agents have been developed and approved to treat patients with EGFR exon 20 insertion mutations, MET exon 14 skipping mutations, and HER2 mutations, contributing to an ever-expanding range of targeted options available to patients with driver mutation– positive NSCLC exon 19 and exon 21. These harder-to-treat mutations account for 4% to 10% of all EGFR mutations in NSCLC and typically present in never-smokers, women, and patients of East Asian descent, explained Catherine A. Shu, MD, at the 17th Annual New York Lung Cancers Symposium. Shu is an associate professor of medicine and clinical director of the Thoracic Medical Oncology Service at the Columbia University Irving Medical Center/NewYork-Presbyterian.

Both amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity) are FDA-approved for use in this population. Amivantamab is a dual EGFR-MET antibody that binds to the extracellular portion of EGFR. Mobocertinib is a small molecule EGFR tyrosine kinase inhibitor that has been chemically optimized from osimertinib (Tagrisso) to be more selective toward exon 20 mutations.

In the pivotal phase 1 CHRYSALIS trial (NCT02609776) of 81 patients who received prior platinum therapy, amivantamab led to an objective response rate (ORR) of 40% per independent review committee (IRC).¹

The median duration of response (DOR) was 11.1 months, and the median progression-free survival (PFS) was 8.3 months.

Regarding insertion location, the 1 patient with an exon 20 insertion in the helical region responded to amivantamab. Patients with near-loop mutations (n = 54) otherwise derived the highest response rate at 41% vs 25% in those with far-loop mutations (n = 8).

Infusion-related reactions were the most common adverse event (AE) reported (any grade, 66%; grade ≥ 3, 3%), occurring predominantly on the first day of treatment. Dermatologic toxicities included rash (any grade, 86%; grade ≥ 3, 4%) and paronychia (any grade, 45%), and MET-related events included hypoalbuminemia (27%) and edema (18%). Dose reduction and discontinuation occurred in 13% and 10% of patients, respectively.

“I’ve also noticed a lot of scalp toxicity, which can be kind of ugly. It’s not something that’s mentioned too much, but it’s something you have to work closely with dermatologists on at your center,” Shu said.

At the approved dose of 160 mg once daily, mobocertinib led to a confirmed ORR of 28% per IRC in 114 platinum-pretreated patients in a phase 1/2 trial (NCT02716116).2 The median DOR and PFS were 17.5 months (95% CI, 8.3-not evaluable [NE]) and 7.3 months (95% CI, 5.5-10.2), respectively.

Primary gastrointestinal toxicities included diarrhea (any grade, 91%; grade > 3, 21%), decreased appetite (35%), and nausea (34%). Similar to amivantamab, rash (any grade, 45%), and paronychia (38%) were common dermatologic toxicities. Regarding cardiac toxicity, QTc prolongation occurred in 11% of patients (grade > 3, 3%), and cardiac failure led to 1 treatment-related death. Notably, dose reductions and discontinuations were more common, at 25% and 17%, respectively. Shu suggested that mobocertinib may be easier to tolerate than amivantamab as it is an oral therapy.

Though not yet approved, CLN-081 is a novel, irreversible oral EGFR inhibitor with selectivity for EGFR exon 20 insertions that has shown promising activity. In a phase 1/2 trial (NCT04036682) of 73 patients, the agent led to a confirmed partial response (cPR) rate of 38.4% and a median DOR of 10 months (95% CI, 6-not calculable).³ Three dose levels were studied, showing comparable activity when administered twice daily: 65 mg or less (cPR rate, 35%), 100 mg (cPR rate, 41%), and 150 mg (cPR rate, 36.4%). Dose reductions and discontinuations were uncommon at doses less than 150 mg.

Across all dose levels, common AEs included rash (any grade, 80%; grade ≥3, 1%), paronychia (any grade, 32%), diarrhea (any grade, 30%; grade ≥ 3, 3%), and fatigue (any grade, 21%).

Another agent in the pipeline is sunvozertinib, a novel oral EGFR exon 20 inhibitor. In a pooled analysis of the WU-KONG 1, 2, and 6 trials, the combined ORR was 52.4% at 300 mg daily (n = 169).4 As with the other 3 agents, common AEs included diarrhea (any grade, 58%; grade ≥ 3, 5.5%), rash (any grade, 39.5%; grade ≥ 3, 1.3%), and paronychia (any grade, 27.7%; grade ≥ 3, 1.3%).

“In the first line, if I don’t have a clinical trial, I’m going to put people on carboplatin/ pemetrexed [Alimta] and maybe bevacizumab [Avastin],” Shu said, clarifying her current practice for patients with EGFR exon 20 insertion mutation–positive NSCLC across lines of treatment. “Second line, I’m putting people mostly on amivantamab because of the higher response rate, although it does mean more inconvenience to the patient with IV infusions. Third line is mobocertinib and then of course, clinical trials.”

MET Exon 14 Skipping Mutations

Next, Shu discussed MET exon 14 skipping mutations, which are found in approximately 3% of patients with NSCLC and are generally more common in older patients, women, and nonsmokers. Because of their heterogeneity, Shu advised using RNA-based assays, as they detect a higher proportion of MET exon 14 skipping cases compared with DNA-based targeted genotyping panels.

Once a mutation has been identified, providers have the option of selecting between tepotinib (Tepmetko) and capmatinib (Tabrecta). The FDA has approved both agents for use in patients with advanced NSCLC with MET exon 14 skipping mutations based on the pivotal, phase 2 VISION (NCT02864992) and GEOMETRY (NCT02414139) trials, respectively. In August 2022, the FDA converted the initial accelerated approval for capmatinib in this setting to a regular approval.

In VISION, tepotinib led to a confirmed, IRC-assessed ORR of 46% at 450 mg daily (n = 99).⁵ The median DOR was 11.1 months (95% CI, 7.2-NE), and the median PFS was 8.5 months (95% CI, 6.7-11). The median overall survival, although not mature, was 17.1 months (95% CI, 12-26.8).

The most common AE was peripheral edema (any grade, 63%; grade >3, 7%), although gastrointestinal effects, including nausea (any grade, 26%; grade >3, 1%) and diarrhea (any grade, 22%; grade >3, 1%), were also notable. Dose reduction occurred in approximately one-third of patients (33%), and 11% discontinued treatment, primarily due to peripheral edema, pleural effusion, and dyspnea.

In GEOMETRY, capmatinib demonstrated an IRC-assessed ORR of 68% (n = 28) in treatment-naïve patients and 41% (n = 69) in previously treated patients.6 The median DOR and PFS were 12.6 months (95% CI, 5.6-NE) and 12.4 months (95% CI, 8.2-NE) in the treatment-naïve subgroup vs 9.7 months (95% CI, 5.6-13) and 5.4 months (95% CI, 4.2-7) in the previously treated group (TABLE^5,6).

In terms of toxicity, peripheral edema was similarly the most common AE (any grade, 51%; grade > 3, 9%). Nausea (any grade, 45%; grade > 3, 2%), vomiting (any grade, 28%; grade > 3, 2%), and diarrhea (any grade, 18%; grade > 3, 1%) were also reported. Dose reduction occurred in 23% of patients and 11% also required treatment discontinuation, primarily due to peripheral edema.

“MET inhibition has a unique signature across all drugs. Mostly it’s this peripheral edema that is most concerning to patients,” Shu said.

“What do I do? For me, it’s pretty straightforward. I start with capmatinib or tepotinib, especially in older patients, because that way they don’t have to come in for infusions. Some people prefer tepotinib for its daily dosing. I’ve been giving capmatinib more because that agent was approved first, but both are good drugs,” Shu said. “Second line would be chemoimmunotherapy. Even in a patient with high PD-L1 expression, for me, the value of having that [oral] drug is so great.”

Shu added that the algorithm may soon change pending further data with amivantamab, which has shown a respectable ORR of 33% (57%) in treatment-naïve patients (n = 7). The median PFS was 6.7 months (95% CI, 2.9-15.3) in a small population of patients with MET exon 14 skipping mutations (n = 46) in the CHRYSALIS study.⁷

HER2 Mutations

Another more recent addition to the growing number of targetable oncogenic drivers in NSCLC is HER2. These mutations account for about 3% of all cases of NSCLC and are typically found in never-smokers and female patients. Additionally, these mutations can be associated with a slightly younger age and higher incidence of brain metastasis.⁸

Fam-trastuzumab deruxtecan-nxki (Enhertu) was approved on August 11, 2022, to treat patients with NSCLC harboring an activating HER2 mutation. It is an antibody-drug conjugate (ADC) consisting of a HER2-directed monoclonal antibody linked to a topoisomerase I payload via a tetrapeptide-based cleavable linker.

The agent first showed benefit in this population in the phase 2 DESTINY-Lung01 trial (NCT03505710),⁸ but the approval was based on findings from the phase 2 DESTINY-Lung02 trial,⁹ which explored the use of the ADC at a lower dose.

In the pivotal study, the 5.4-mg/kg dose of trastuzumab deruxtecan led to a confirmed ORR of 53.8% (95% CI, 39.5%-67.8%) compared with 42.9% (95% CI, 24.5%-62.8%) with the 6.4-mg/kg dose. The median DOR at the lower dose was 8.7 months (95% CI, 7.1-NE).

Fewer AEs were also reported in the lower-dose arm than in the higher-dose arm (any grade, 92.1% vs 100%, respectively; grade ≥ 3, 31.7% vs 58.0%). Interstitial lung disease was a toxicity of interest with the ADC, and rates were also lower at the 5.4-mg/kg dose compared with the 6.4-mg/kg dose (5.9% vs 14.0%, respectively).

Beyond trastuzumab deruxtecan, the FDA considered a new drug application for poziotinib, an irreversible pan-ERBB inhibitor, as a possible treatment for patients with previously treated locally advanced or metastatic NSCLC with a HER2 exon 20 insertion mutation.

The application was supported by findings from a cohort of the phase 2 ZENITH20 trial (NCT03318939), which showed an ORR of 35.1% and a disease control rate of 82.4%. The median DOR was 5.1 months and the median PFS was 5.5 months.¹⁰

AEs were common with the agent, however, including rash in 91.1% of patients, diarrhea in 82.2%, and stomatitis in 68.9%.

Due to its high toxicity, short durability of response, and inadequate dosage optimization, among other reasons, the FDA’s Oncologic Drugs Advisory Committee ultimately voted that the benefits of poziotinib did not outweigh its risks and the FDA subsequently denied the approval.¹¹

<sub>REFERENCES:
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_{2. 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}

_{3. Yu HA, Tan DSW, Smit EF, et al. Phase (Ph) 1/2a study of CLN- 081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (Ins20). J Clin Oncol. 2022;40(suppl 16):9007. doi:10.1200/ JCO.2022.40.16_suppl.9007}

_{4. Shu C. The new kids on the block: EGFR exon 20 and MET exon 14. Presented at: 17th Annual New York Lung Cancers Symposium; November 12, 2022; New York, New York.}

_{5. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407}

_{6. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.10156/NEJMoa2002787}

_{7. Krebs M, Spira AI, Cho BC, et al. Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: updated results from the CHRYSALIS study. J Clin Oncol. 2022;40(suppl 16):9008. doi:10.1200/JCO.2022.40.16_suppl.9008}

_{8. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431}

_{9. Goto K, Sang-We K, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{10. Le X, Cornelissen R, Garassino M, et al. Poziotinib in non-small-cell lung cancer harboring HER2 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. J Clin Oncol. 2022;40(7):710-718. doi:10.1200/JCO.21.01323}

_{11. Spectrum Pharmaceuticals receives complete response letter from U.S. Food and Drug Administration for poziotinib; Reaffirms focus on the commercialization of ROLVEDON (eflapegrastim-xnst) injection. News release. Spectrum Pharmaceuticals. November 25, 2022. Accessed November 28, 2022. https://bwnews.pr/3FfAx0j}