Advancing Targets: Latest FDA Approvals, Strategies in NSCLC Treatment Unveiled at ASCO 2024

Hippensteele,Alana;

During a presentation on advancements in the treatment of lung cancer at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Matthew A. Gubens, MD, MS, FASCO, a thoracic oncologist at the University of California, San Francisco, explained that an important mantra in the treatment of metastatic non–small cell lung cancer (NSCLC) with oncogene addiction/driver mutations is that one cannot treat a target that has not yet been identified. Specifically, identification may include tumor and liquid biopsy or DNA-and/or RNA-based next-generation sequencing (NGS).¹

“The mantra ‘You can't treat a target you haven’t identified’ concerns the idea of interdisciplinary teams [working to] get adequate tissue up front and adequate testing in a timely way to get our patients to the treatments that can improve their quality of life and length of life,” Gubens said. “Of course, logistics are key.”¹

Currently, there are 9 genomic alterations in NSCLC that have FDA-approved treatments, according to Gubens. These alterations include EGFR, ALK, ROS1, BRAF, NTRK, RET, MET, KRAS, and HER2. Of the currently FDA-approved treatments for these indications, 3 have had FDA approval changes since ASCO 2023, including a new ROS1 agent (repotrectinib [Augtyro; Bristol Myers Squibb]), a new BRAF combination treatment (encorafenib [Braftovi; Pfizer] plus binimetinib [Mektovi; Pfizer]), and a newly available treatment for HER2 immunohistochemistry without gene amplification (IHC3+, fam-trastuzumab deruxtecan-nxki [Enhertu, Daiichi Sankyo, Inc]).¹

“These 3 FDA approval changes in the last year bring us up-to-date with newer approaches that you may not have had a chance to use yet,” Gubens said. “[Also, you should have a] low threshold to biopsy at progression to detect actual resistance mechanisms [in this setting].”¹

Gubens explained that 2 drugs were approved for ROS1 NSCLC until recently: crizotinib (Xalkori; Pfizer) and entrectinib (Rozlytrek; Genentech). Crizotinib was approved in 2016 based on the results of the multicenter, single-arm phase 1 Study 1001 (n=50), which showed an overall response rate (ORR) of 66% (95% CI: 51%, 79%), and a median duration of response (mDoR) of 18.3 months (95% CI: 12.7 months, not reached). Entrectinib was approved in 2019 for the treatment of adults with ROS1-positive, metastatic NSCLC based on results from the integrated analysis of the pivotal phase 2 STARTRK-2 (NCT02568267), phase 1 STARTRK-1 (NCT02097810), and phase 1 ALKA-372-001 (NCT03961100) trials, and data from the phase 1/2 STARTRK-NG (NCT02650401) study. Efficacy in ROS1-positive metastatic NSCLC was investigated in 51 adult patients, with 90% receiving entrectinib at 600 mg orally once daily. ORR was 78% (95% CI: 65, 89) and DoR was 12 months or longer for 55% of patients.¹

“Both [were approved] on small datasets with very respectable response rates and good [DoRs]. This was definitely a good first-line approach,” Gubens said. “[Further,] lorlatinib [Lorbrena; Pfizer] is not FDA approved for ROS1, but it does have activity and is listed on [National Comprehensive Cancer Network]. It's been our go-to in the second-line setting with a response rate of 35% in patients previously on crizotinib with a good [DoR] at 14 months.”¹

However, repotrectinib was FDA approved on November 15, 2023, for locally advanced or metastatic ROS1-positive NSCLC. Notably, this is the first FDA approval that includes patients with ROS1-positive NSCLC who were previously treated with a ROS1 tyrosine kinase inhibitor (TKI), as well as patients who are TKI naive.¹

The approval was based on global, multicenter, single-arm, open-label, multi-cohort TRIDENT-1 trial (NCT03093116), which evaluated the efficacy of repotrectinib in 71 ROS1 TKI-naïve patients who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy, and 56 patients who received 1 prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy. In the ROS1 TKI-naive cohort, confirmed ORR was 79% (95% CI: 68, 88), and in those who received a prior ROS1 inhibitor, ORR was 38% (95% CI: 25, 52). Further, mDOR was 34.1 months (95% CI: 25.6, not evaluable) and 14.8 months (95% CI: 7.6, not evaluable), respectively.1,2 The most common (>20%) adverse events (AEs) were dizziness (62%), dysgeusia (53%), constipation (38%), anemia (38%), and paresthesia (34%).¹

“[This is a] suite of [AEs] you really have to be familiar with if you're going to be prescribing this drug to your patients,” Gubens said. “But this is a very exciting new first-line option or an option at resistance, but watch for that neurotoxicity.”¹

Gubens noted that repotrectinib was designed to inhibit ROS1 as well as TRK fusion, including in the presence of resistance mutations such as solvent-front mutations.¹

“This is important because, even though it is not approved for TRK at this point, it doesn't evoke some of the [AEs] that any TRK inhibitor is involved with,” Gubens said.¹

Key Takeaways

FDA-Approved Genomic Alterations: There are currently 9 genomic alterations in NSCLC with FDA-approved treatments: EGFR, ALK, ROS1, BRAF, NTRK, RET, MET, KRAS, and HER2. Three recent FDA approvals since ASCO 2023 include a new ROS1 agent (repotrectinib), a BRAF combination treatment (encorafenib plus binimetinib), and a treatment for HER2 IHC3+ (fam-trastuzumab deruxtecan-nxki).
ROS1 NSCLC Treatments: Crizotinib and entrectinib were initially approved based on high response rates from small datasets. Repotrectinib was recently approved for both TKI-naive and previously treated patients, showing high efficacy and notable adverse events (AEs) such as dizziness and dysgeusia.
BRAF V600E NSCLC Treatments: Dabrafenib plus trametinib has been the standard treatment with significant response rates. New approval for encorafenib plus binimetinib shows promising results with somewhat fewer severe toxicities compared to previous treatments.
HER2 IHC 3+ NSCLC Treatments: Fam-trastuzumab deruxtecan-nxki was approved for HER2+ solid tumors based on the DESTINY-Lung01 trial, demonstrating significant efficacy but also a high rate of pneumonitis, a serious AE that requires careful management.
Treatment Approach and Monitoring: Matthew A. Gubens, MD, MS, FASCO, emphasized the need for interdisciplinary teams to ensure adequate tissue samples and timely testing. A low threshold for re-biopsy at progression is necessary to detect resistance mechanisms. Monitoring for specific AEs and managing them appropriately is crucial for patient safety and treatment efficacy.

Although BRAF V600E TKIs are much more developed in the melanoma space, dabrafenib (Tafinlar; Novartis) plus trametinib (Mekinist;Novartis) was approved in 2017 for BRAF V600E mutation-positive metastatic NSCLC (n=36 treatment naive). The approval was based on Study BRF113928 (NCT01336634), which included 93 patients. In the previously treated group (n=57), ORR was 63% (95% CI: 49%, 76%) with a mDoR of 12.6 months (95% CI: 5.8, not estimable [NE]). In the treatment-naive group (n=36), ORR was 61% (95% CI: 44%, 77%) and median DoR was NE (95% CI: 6.9, NE); however, 59% of responders had a DoR greater than 6 months. The ORR for patients who received dabrafenib alone was 27% (95% CI: 18%, 38%) and mDoR was 9.9 months.^1,3

“Again, very small dataset but a robust response rate,” Gubens said. “[Dabrafenib plus trametinib] has been the standard of care for several years.”¹

However, Gubens noted that on October 12, 2023, the FDA approved encorafenib plusbinimetinib for the treatment of BRAF V600E metastatic NSCLC.1,3 The approval was based on data from the phase 2 open-label, multicenter, single‑arm PHAROS trial (NCT03915951), which examined the combination therapy in both treatment-naive and previously treated patients. In treatment-naïve patients (n=59), ORR was 75% (95% CI: 62, 85), and 59% of the patients responded for at least 12 months; however, mDoR was NE for this group at the time of data cutoff. In previously treated patients (n=39), ORR was 46% (95% CI: 30, 63), and 33% of the patients responded for at least 12 months. Further, the mDoR for this group was 16.7 months (95% CI: 7.4, NE).^1,4

The most common (≥25%) all cause AEs for the combination therapy were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. Notably, 17% of patients who experienced an AE permanently discontinued binimetinib, and 16% permanently discontinued encorafenib. Serious AEs occurred in 38% of patients, with 2% or more of AEs including hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, and pneumonia (3.1% each); arrhythmia, device-related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal AEs occurred in 2% of patients, including intracranial hemorrhage and myocardial infarction (1% each).^1,4

“I would point out that it at least numerically appears to have somewhat fewer grade 3 and 4 toxicities, and somewhat less dose reduction and discontinuation. Notably, I do get to know some of the quirky [AEs] of each of these drugs, and pyrexia has effects that are not life threatening, but are very frustrating for patients,” Gubens said. “But the rate of pyrexia is significantly lower in this regimen, so I've actually switched a few patients [to this combination therapy].”¹

For HER2 NSCLC, fam-trastuzumab deruxtecan-nxki was approved on April 5, 2024, for the treatment of adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors who have received prior systemic treatment with no satisfactory alternative treatment options.¹

“Now, we've already had our first 2 mutation approvals for fam-trastuzumab deruxtecan-nxki, which was based on the DESTINY-Lung01 trial [NCT03505710] with an open-label, basket, phase 2 design with 91 patients with [NSCLC],” Gubens said. “The dose, I should note, on the trial was 6.4 mg per kg, but the FDA label is 5.4 mg per kg, and that's important from a toxicity perspective.”¹

In the DESTINY-Lung01 trial, the median duration of follow-up was 13.1 months (range, 0.7 to 29.1), with ORR in 55% of patients (95% confidence interval [CI], 44 to 65). The mDoR was 9.3 months (95% CI, 5.7 to 14.7), median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). Additionally, the trial data showed that the safety profile was generally consistent with previous studies, and grade 3 or higher AEs occurred in 46% of patients. The most common AE was neutropenia (in 19%), with adjudicated pneumonitis occurring in 26% of patients, resulting in 2 deaths. The media onset of pneumonitis was 141 days.^1,6

“Many of you treat more than just lung cancers, and you may have used this drug quite a bit in the breast cancer space. Really important to note that pneumonitis, almost more than cardiotoxicity, frightens me in this patient population. There's a 26% adjudicated pneumonitis rate in this trial, and these ranges in grades can be serious, and they can also be tough to diagnose because we have a differential that includes pneumonia, but also includes progression,” Gubens said. “You may want to have a low [threshold] to work these up and evaluate them and take them seriously with dose pauses, evaluation for pulmonology, and even consideration of steroids.”¹

For the subset of patients on fam-trastuzumab deruxtecan-nxki in the DESTINY-Lung01 trial who have HER2 expression or HER2 mutation, expression data was inconsistent, according to Gubens.¹

“Quite a few of these patients have no HER2 expression or 1+, 2+, or 3+, so it's all over the map,” Gubens said. “Actually, of the patients who were assessable for amplification, only a few had amplification. So, these seem to be 2 different entities, and that's important because now we're potentially going to treat these differently as well.”¹

Furthermore, aside from the HER2 mutated patients in DESTINY-Lung01 trial, there were also 2 cohorts of patients with HER2 overexpression in their tumors, according to Gubens. The patients with HER2 overexpression were treated at 2 dose levels (5.4 mg/kg and 6.4 mg/kg) with IHC3+ or IHC2+, and they notably could not have a HER2 mutation, so they are a distinct subset, Gubens explained.¹

During the trial, patients with HER2 overexpression were assigned to cohorts sequentially, with cohort 1 receiving fam-trastuzumab deruxtecan-nxki at 6.4 mg/kg and cohort 1A receiving trastuzumab deruxtecan at 5.4 mg/kg, both administered intravenously once every 3 weeks. As of data cutoff on December 3, 2021, the median treatment duration was 4.1 months in cohort 1 and 5.5 months in cohort 1A, with median follow-up of 12.0 months and 10.6 months, respectively. Confirmed ORR was 26.5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34.1% (20·1-50·6; 14 of 41; 2 complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent AEs (TEAEs) at grade 3 or greater were neutropenia (12 [24%] of 49 in cohort 1, 0 in cohort 1A), pneumonia (6 [12%] and 2 [5%], respectively), fatigue (6 [12%] and 3 [7%], respectively), and disease progression (6 [12%] and 4 [10%], respectively). Drug-related TEAEs at grade 3 or greater occurred in 26 (53%) of 41 patients in cohort 1 and 9 (22%) of 49 patients in cohort 1A. Drug-related serious AEs were reported in 10 (20%) patients and 3 (7%) patients, respectively, with deaths occurring because of TEAEs in 10 (20%) patients in cohort 1 (disease progression in 6 (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in 1 [2%] patient each), and in 7 (17%) patients in cohort 1A (due to disease progression in 4 (10%) patients and dyspnoea, malignant neoplasm, and sepsis in 1 (2%) patient each).^1,7

Furthermore, drug-related pneumonitis occurred in 10 (20%) patients in cohort 1 (2 [4%] grade 1, 5 [10%] grade 2, and 3 [6%] grade 5) and 2 (5%) patients in cohort 1A (1 [2%] grade 2 and 1 [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 pneumonitis.^1,7

“What we see is that even though the response rates are not quite as robust at 26.5% and 34.1%, that compares very favorably to the second-line therapy for these patients who are otherwise coming off of chemoimmunotherapy,” Gubens said. “These data [from DESTINY-Lung01] combined with [DESTINY-CRC02 (NCT04744831)] data and [DESTINY-PanTumor02 (NCT04482309)] data led to investigative tumor agnostic FDA approval. So, for all solid tumors with HER2 expression and IHC3+ or higher who've received prior systemic therapy, patients are eligible for fam-trastuzumab deruxtecan-nxki. So very important to keep this in mind while also noting that this evaluation would not necessarily be part of your NGS, as you actually have to ask for it specifically, either on the primary specimen or on a resistant specimen. So, keep that in mind as you're considering options for your patients.”¹