Molecular Testing Benefits Patients as Targeted Therapies Continue to Evolve for Metastatic NSCLC

In a recent analysis published in <em>JAMA</em>, data were evaluated from a collection of clinical trials and analyzed for important takeaways in the testing and treatment of patients with non&ndash;small cell lung cancer. The authors stress the importance of molecular testing in patients with NSCLC as more targeted therapies become available.&nbsp;<br /> &nbsp;

Gregory J. Riely, MD, PhD

The importance of molecular testing in patients with non—small cell lung cancer (NSCLC) continues to grow as more targeted therapies become available. By conducting molecular testing, physicians can select treatments that are more personalized to the patient’s individual disease.

Patients diagnosed with metastatic NSCLC are recommended to undergo molecular testing to determine the presence of molecular alterations that can guide treatment decisions. The alterations that should be tested for currently includeEGFRmutations,ALKrearrangements,ROS1rearrangements,BRAFV600E mutations, andNTRKfusions, as well as PD-L1 expression, as these may predict responses to currently available FDA-approved treatments.

In a recent analysis published inJAMA, data were evaluated from a collection of clinical trials conducted between January 1, 2013, and May 1, 2019, and analyzed for important takeaways in the testing and treatment of patients with NSCLC.

Both randomized trials and nonrandomized trials that led to changes in standard treatments or regulatory approvals in NSCLC were evaluated, and guidelines from major professional societies were also reviewed. Investigators looked at the role of molecular testing in these trials, as well as the effectiveness of various targeted therapies that are impacted by identifying these alterations.

Molecular Testing

Kathryn C. Arbour, MD

“Testing, such as hybridization capture—based next-generation sequencing platforms, allows oncologists to obtain comprehensive molecular test results with 1 assay,” authors Kathryn C. Arbour, MD, and Gregory J. Riely, MD, PhD, noted in the published report. “These approaches may be more cost-effective and reduce waiting time for patients compared with single-gene assays.”

For patients with insufficient tissue, plasma circulating tumor DNA (ctDNA) is also an emerging option for identifying alterations. Plasma ctDNA has a detection rate of over 75% and a concordance rate of over 95%, depending on the platform used, but the results from these tests can also be obtained much quicker than with a tissue biopsy. However, while additional testing is not necessary if ctDNA is positive, 20% of patients with negative ctDNA have molecular alterations that impact response to treatment.

“A combination of plasma testing and tissue testing may provide the greatest sensitivity for identifying molecular alterations responsive to treatment,” the study authors wrote. “Although plasma testing has demonstrated unique value in patients for whom tumor tissue is not available, the standard of care consists of testing tumor tissue, and this should be performed for all patients with metastatic NSCLC when feasible.”

The authors also stressed the importance of testing PD-L1 tumor proportion score through immunohistochemistry assays as a biomarker for potential response to immune checkpoint inhibitors.

Approved Targeted Treatments

For patients with metastatic NSCLC, combinations of platinum-based chemotherapies have been able to reduce symptom burden and improve quality of life and survival compared with single-agent chemotherapy. Cytotoxic chemotherapy regimens also benefit patients with a limited ECOG performance status, but these agents are generally associated with significant toxicities. In recent years, research has focused on the development of targeted therapies for patients whose tumors have targetable mutations.

Approximately 20% of patients with NSCLC present with anEGFRmutation, including L858R mutations or exon 19 deletions most commonly. Treatment options for these patients include EGFR tyrosine kinase inhibitors (TKIs), including first-generation TKIs gefitinib (Iressa) and erlotinib (Tarceva), and second-generation TKIs afatinib (Gilotrif) and dacomitinib (Vizimpro). However, approximately 60% of patients experience treatment resistance with these agents in the form of an acquiredEGFRT790M mutation.

Osimertinib (Tagrisso), a third-generationEGFRTKI, has demonstrated the ability to overcome this resistance and induce tumor responses. Based on findings from a randomized clinical trial, upfront osimertinib led to a progression-free survival (PFS) of 18.9 months as initial treatment, compared with 10.2 months for patients who initially received a first- or second-generation TKI (HR, 0.46; 95% CI, 0.37-0.57;P<.001). Similar benefit in PFS with initial osimertinib treatment was also noted in patients with central nervous system metastases.

Rash was the most severe adverse event (AE) noted with all EGFR TKIs. Seventy-eight percent of patients treated with a first-generation TKI had any rash, while 38% had moderate or severe rash. However, 58% of patients treated with osimertinib had any rash and 10% has moderate to severe rash.

About 5% of patients with metastatic NSCLC have been found to have overexpression of the ALK protein. Crizotinib (Xalkori), which targets bothMETandALKreceptor tyrosine kinases, was the first TKI to achieve tumor responses in this subset of patients. Newer and more potent ALK TKIs, such as alectinib (Alecensa), ceritinib (Zykadia), and brigatinib (Alunbrig), have proven effective in treating patients with resistance to crizotinib, according to early-phase clinical trials.

Next-generation ALK TKI alectinib demonstrated superiority to crizotinib in a randomized phase III trial of patients with metastaticALK-positive NSCLC. The median PFS in the arm that received alectinib was 34.8 months versus 10.9 months with crizotinib.

More recently, in 2018, lorlatinib (Lorbrena), a third-generation ALK inhibitor, was approved for the treatment of patients withALK-positive NSCLC and progressive disease following treatment with at least 2 prior ALK TKIs, based on data from a phase II multicohort trial.

Approximately 1% of patients with NSCLC haveROS1rearrangements. BecauseROS1andALKshare similar homologies, ALK TKIs have been effective in the treatment of this subset of patients. Crizotinib, specifically, led to a 72% response rate in patients withROS1-rearranged NSCLC and a median PFS of 19 months. Crizotinib is the only FDA-approved agent available in this setting.

BRAFV600E mutations are found in 1% to 2% of patients with lung adenocarcinoma.BRAFinhibitors dabrafenib (Tafinlar) and vemurafenib (Zelboraf) have yielded short responses as single agents in this patient population, but a phase II clinical trial showed that the combination of aBRAFinhibitor and aMEKinhibitor, such as trametinib (Mekinist), induced a response rate of 64% with a median PFS of 11 months.

Emerging Targets and Treatments

Approximately 4% of patients with NSCLC have aMETexon 14 skipping mutation; crizotinib demonstrated a decrease in tumor size and a radiographic response rate of 35% in preliminary findings for this subset of patients. There are currently no FDA-approved agents for patients harboring this mutation, but the National Comprehensive Cancer Network (NCCN) Guidelines include crizotinib as a treatment option for this subset of patients.

HER2mutations are seen in about 2% of patients with lung cancers, where the HER2-targeted antibody—drug conjugate (ADC) trastuzumab emtansine (T-DM1; Kadcyla) can achieve tumor responses. Trastuzumab emtansine led to a 44% response rate and median PFS of 5 months in these patients, suggesting thatHER2mutations may be a better biomarker for HER2-directed therapies than protein overexpression.

RETrearrangements occur in 1% to 2% of patients with NSCLC. There are multiple multikinase inhibitors available, such as cabozantinib (Cabometyx), that can target RET, which have demonstrated modest efficacy in this subset of patients. Cabozantinib has demonstrated a response rate of 28% in patients withRET-rearranged NSCLC and a median PFS of 5.5 months. Vandetanib (Caprelsa) has also shown a response rate of 18% in these patients and a median PFS of 4.5 months. However, more selective RET inhibitors are currently undergoing investigation.

Less than 1% of patients with NSCLC present with anNTRKgene alteration. Larotrectinib (Vitrakvi) has been approved for the treatment of these patients after demonstrating a response rate of 75% and a 12-month PFS rate of 55% inNTRK-altered cancers, regardless of the primary site. Four patients with lung cancer were included in the data that led to this approval, while other patients included had a variety of cancer types, such as soft tissue sarcoma and salivary gland tumors.

Approved Immunotherapies

The advent of PD-1/PD-L1 immune checkpoint inhibitors has changed the way patients with metastatic disease are treated. Initially, this therapy was approved by the FDA following initial treatment with a platinum-based chemotherapy. However, PD-1 and PD-L1 have since proven their efficacy in the frontline setting for patients with metastatic NSCLC.

Patients were randomized to receive either pembrolizumab (Keytruda), an anti—PD-1 antibody, or platinum-based chemotherapy in a phase III trial of patients with a PD-L1 score of 50% or greater who were notEGFR-orALK-positive. Patients that received pembrolizumab had an improved radiographic response of 45%, an improved PFS of 10.3 months, and an improved median overall survival (OS) of 30.0 months compared with 28%, 6.0 months, and 14.2 months in the control arm, respectively. Additionally, pembrolizumab was also associated with a lower frequency of severe AEs.

Similar immune-related AEs occur with pembrolizumab to that of any immune checkpoint inhibitor, such as pneumonitis, colitis, and thyroiditis. Any-grade immune-related AEs occur in 25% to 30% of patients, while the rate of grade 3 to 5 AEs has been low, in around 8% to 10% of patients, according to data pooled from clinical trials. Recommendations for the management of immune-related AEs have been released by several associations to assist physicians in dealing with these toxicities effectively.

The most effective treatment for patients with nonsquamous NSCLC and less than 50% PD-L1 has been found to be an immune checkpoint inhibitor in combination with chemotherapy. Benefit with this combination regimen was first observed in a randomized phase II clinical trial of the combination of carboplatin, pemetrexed, and pembrolizumab in patients with metastatic nonsquamous NSCLC. The findings were confirmed by a randomized phase III of pembrolizumab plus pemetrexed and cisplatin or carboplatin versus chemotherapy alone in patients with nonsquamous NSCLC. The combination regimen led to an improved radiographic response rate of 48%, PFS of 8.8 months, and an OS rate of 69% at 12 months versus 19%, 4.9 months, and 49% in the chemotherapy-alone arm, respectively.

Anti—PD-L1 antibody atezolizumab (Tecentriq) was also effective in combination with chemotherapy for the frontline treatment of patients with advanced, nonsquamous NSCLC. Patients that received atezolizumab plus paclitaxel, carboplatin, and bevacizumab (Avastin) had an improved median PFS of 8.3 months versus 6.8 months in patients that received the 3 drugs without atezolizumab. The atezolizumab arm also achieved an improved OS of 19.2 months versus 14.7 months in the control arm. The benefits noted in this clinical trial remained irrespective of PD-L1 tumor proportion score.

Stage III NSCLC is potentially curable with multimodality therapy, including induction chemotherapy followed by surgery or a combination of chemotherapy and radiation. However, the cure rate is less 20%. Many clinical trials are currently investigating the potential role of immune checkpoint inhibitors in this patient population, as well as adjuvant immunotherapy following surgery or neoadjuvant therapy.

Checkpoint inhibitors following curative-intent concurrent chemoradiation has shown benefit in patients with stage III nonmetastatic NSCLC. In a randomized phase III clinical trial, patients received either a placebo or durvalumab (Imfinzi) for 1 year following chemoradiation. Durvalumab led to an improved tumor response rate, PFS, and OS. However, a post-hoc analysis showed that the benefit may be less clear in patients with PD-L1—negative disease, suggesting that the use of durvalumab as a consolidation therapy in PD-L1–negative patients must be evaluated further. Nonetheless, the risk of severe AEs was higher in those who received durvalumab. Most notable, patients in the durvalumab arm had a higher rate of pneumonitis (12.6%) versus those in the placebo arm (7.7%).

Over the last decade, treatment options for NSCLC have continued to expand. New targeted agents and checkpoint inhibitors continue to be investigating for the treatment of patients with metastatic NSCLC harboring different molecular alterations or biomarkers that could impact treatment response.

“Treatment goals have evolved to preventing the development of resistance to targeted therapy,” the study authors concluded. “These advances are substantial, but long-term durable responses remain uncommon for most patients…. The goal of NSCLC research is to understand and address mechanisms of resistant and refractory disease in patients with advanced disease and, ultimately, to increase cure rates.”


Arbour KC, Riely GJ. Systemic Therapy for Locally Advanced and Metastatic Non—Small Cell Lung Cancer: A Review.JAMA.2019;322(8):764-774. doi: 10.1001/jama.2019.11058.