The Case for Targeted Testing for Activating and Actionable Mutations

By Dhaval Shah, MD, and Gregory Masters, MD, FASCO, FACP

Lung cancer remains the most common cause of cancer mortality worldwide,¹ and most patients present with advanced disease, limiting the potential for curative therapy. Recent advances in understanding the molecular biology of lung cancer, particularly the discovery of genetic driver mutations in non-squamous non-small cell lung carcinoma (NSCLC), have led to the development of unique targeted therapies, often achieving remarkable responses in patients with these genetic alterations.²

Guidelines from the College of American Pathologists and International Association for the Study of Lung Cancer in a 2013 paper recommended testing for EGFR and ALK mutations.³ Since then, however, new actionable mutations have been identified, leading to U.S. Food and Drug Administration (FDA) approval of additional targeted therapies. Data support the value of molecular testing for these actionable mutations in patients with advanced non-squamous NSCLC, but the optimal technique has been debated.

Hotspot testing in advanced NSCLC focuses on testing for unique, identified gene alterations that have been correlated with an effective targeted therapy, while more broad-based testing with next-generation sequencing (NGS) looks at many more potential gene alterations, up to several hundred genes, to characterize the tumor genetic profile. At this time, however, the utility of NGS sequencing as initial testing for all patients with NSCLC has not been proven.

The first driver mutations detected and extensively studied in advanced NSCLC were mutations of the epidermal growth factor receptor (EGFR). Mutations of EGFR had both predictive and prognostic significance. EGFR mutations are seen in about 15% of patients with lung adenocarcinoma in the U.S., but the incidence is higher in women, non-smokers and patients of Asian origin.⁴ Trials have shown the effectiveness of tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.^5,6 Early trials of EGFR inhibitors, however, showed limited activity in unselected patients.^7,8 With up-front EGFR mutation testing, however, phase III clinical trials showed the superiority of EGFR inhibitors over chemotherapy as first-line treatment in patients with EGFR-mutated advanced NSCLC.

In 2007, researchers in Japan discovered anaplastic lymphoma kinase (ALK) gene rearrangement as a potential target.⁹ALK rearrangement is seen in 3% to 7% of patients with advanced lung adenocarcinoma. This led to the development of crizotinib, an ALK tyrosine kinase inhibitor that showed a response rate of 60% with progression-free survival of 8 to 10 months,¹⁰ establishing targeted therapy with ALK inhibitors as standard first-line treatment for ALK-positive NSCLC.

Similarly, ROS-1 mutations are a target for treatment with crizotinib.¹¹ Patients with ROS-1 mutations treated with crizotinib experienced high response rates and improvements in survival, helping to establish crizotinib as the first-line treatment in this population.¹²

BRAF inhibition with dabrafenib and trametinib has also been approved for use in patients with BRAF V600E-mutated advanced NSCLC based on a multicenter trial in 93 patients. The overall response rate was an encouraging 63%.¹³

These studies support testing of advanced non-squamous NSCLC tumors for these four actionable mutations for which FDA-approved drugs are available to treat patients with advanced NSCLC.

More comprehensive molecular profiling of tumors with NGS, however, remains controversial. The concept is interesting, with the hope of finding more clinically meaningful mutations, but data to support universal NGS testing are incomplete.

The NCI-sponsored MATCH (Molecular Analysis for Therapy Choice) trial evaluates the role of NGS in patients with refractory advanced solid tumors who have exhausted standard options. Patients with an identified mutation are then “matched” to a targeted drug based on their tumor genomic profile. This trial continues to accrue and will help inform the role for NGS testing on a broader scale.

ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study is a non-randomized clinical trial which evaluates the role of commercially available targeted drugs for treatment of cancers with a potentially actionable mutation for which that agent is not yet approved.

Further investigating the role of broader molecular testing, an analysis of a large series from the Johns Hopkins molecular tumor board was reported. The criteria for selection of actionable mutations were similar to those used in the NCI MATCH study.¹⁴ In this series, out of the 155 eligible patients, 24 patients (15%) received a targeted drug either off label or on a clinical trial. However, only 6% (10 patients) had a benefit that lasted at least 6 months. While encouraging for those responding patients, the limited success highlights the limitations of comprehensive molecular testing.

In the MOSCATO trial, 1,035 patients had molecular testing, allowing 199 patients to be treated with matched targeted therapy. Of these, 22 patients had an objective response, leading to the authors’ conclusion that only 7% of successfully screened patients achieved a benefit with use of this genomic testing approach.¹⁵

Molecular testing for proven actionable mutations has led to clinically meaningful treatment options that improve response rate, quality of life, and survival. This remains the standard of care for selecting patients who will derive a benefit from molecular targeted therapies.

NGS testing continues to hold promise in patients with refractory disease, but its broader use for initial molecular profiling should be incorporated into clinical trials, where lessons will be learned and results can be scrutinized.

Premature implementation of universal NGS testing at initial diagnosis in NSCLC may lead to false hope for both patients and clinicians. The potential opportunity cost of foregoing established and effective (although limited) chemotherapy treatment should not be overlooked.¹⁶

Ultimately, we all want our patients to have the best outcome possible. We must continue to explore the role for advanced NGS testing through clinical trials. But as we care for our patients and train the next generation of oncologists, let us not lose sight of the importance of an evidence-based approach for both treatment and testing in patients with advanced NSCLC.

References

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The Case for Next-Generation Sequencing

By Travis Osterman, DO, MS, and Leora Horn, MD, MS

The treatment landscape of advanced NSCLC has changed dramatically in the past decade. The recommendation for first-line therapy is driven by histologic evaluation, PD-L1 expression, and molecular testing. While some practices may choose to limit molecular testing to single gene alterations with an FDA-approved first-line therapeutic indication (EGFR, ALK, ROS1, and BRAF), there are several reasons to engage in broader genomic profiling covering hundreds of alterations. In most practices, broader genomic profiling or “multiplex testing” is commonly performed via NGS or allele-specific polymerase chain reaction (PCR).

The most critical reason to consider multiplex testing via NGS is tissue preservation. Bypassing single gene testing in favor of upfront multiplex testing is by far a more efficient use of tumor tissue. For example, by initially testing just the four alterations mentioned above (EGFR, ALK, ROS1, and BRAF), there may not be sufficient tissue for all four individual tests as well as PD-L1 expression. In this scenario, repeating a biopsy is a costly option. In addition to subjecting the patient to another procedure, the associated risks of complication, and the financial burden, the provider must wait for the results to return—potentially delaying treatment decisions by weeks.

Another common argument for NGS is to identify patients for clinical trials. While patients with tumors that have alterations in RET, MET, HER2, FGFR, NTRK1, PIK3CA, and RAS pathways do not currently have FDA-approved therapies, agents targeting these pathways are being evaluated in the setting of clinical trials. A multitude of prior studies have demonstrated improved response rate, progression-free survival, and overall survival in patients with a known driver mutation, such as EGFR, treated with a targeted therapy compared to chemotherapy.^1-10 Therefore, the results of comprehensive NGS may allow a clinician to offer a patient a better treatment option prior to embarking on therapy and continue to be relevant after treatment with immunotherapy, cytotoxic chemotherapy, or both. As treatment options continue to evolve for patients with NSCLC, it is increasingly important for oncologists to consider all possible therapies a patient may be eligible to receive during treatment of their disease.

A perceived barrier to NGS panel testing is delay in starting therapy due to the length of time required for testing. Processing times for NGS are variable and depend on several factors. Generally, clinical testing is performed in a CLIA-certified molecular pathology laboratory where testing is completed in approximately 2 weeks from the time the tissue is received. In practices that have “reflex” or automatic testing of lung cancer specimens, this is normally within about a week of a patient’s first visit with their oncologist. The greater barrier is ensuring testing is completed. A study conducted a year prior found that despite the availability of FDA-approved therapies, only 68% and 59% of patients in a large community practice were being tested for both EGFR and ALK.¹¹

Insurance coverage for initial NGS panel testing continues to evolve.¹² Two recent studies found that the overall cost of NGS testing compares favorably to single gene testing. A 2016 Dutch cost analysis study compared the cost of single gene testing to NGS panel testing for NSCLC. The authors found that while from 2012 to 2015, single gene testing was more cost effective, from 2015 to 2020, NGS testing will be more cost effective.¹³ This change is due to multiple factors, but based largely on improving testing efficiency and decreased need for multiple tests (i.e., getting single gene testing for the first-line treatment decision and getting NGS for clinical trial evaluation later). A United Kingdom study found similar results that a 46-gene panel was more cost effective than performing more than two or three single gene tests.¹⁴

In addition to all the direct benefits of NGS panel testing, an indirect benefit is the wealth of information that can be learned by studying the genetic profiles of large numbers of patients. Registries such as the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) are supporting clinical and translational research and discovery by pooling molecular data from multiple institutions.¹⁵

In conclusion, performing multiplex NGS in patients with metastatic NSCLC at the time of diagnosis is standard practice at many centers across the United States and globally. NGS testing does not significantly delay treatment and can potentially save a patient an additional biopsy and provide them with therapeutic options they would not have otherwise known. There is evidence to support that initial NGS panel testing is more cost effective today than two or three single gene tests. Finally, NGS testing supports the broader research enterprise and scientific discovery, in an effort to advance cancer care.

References

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