Next-Generation Sequencing Can Improve Treatment Decisions, But Community Uptake Remains Delayed

Kashyap Patel, MD

Precision medicine has afforded oncologists the opportunity to develop individualized approaches to treat non—small cell lung cancer (NSCLC), one of the most devastating malignant disorders, which until the past decade was thought to be invariably fatal within months. These advances are welcome, but rapid development of complex therapeutic options has led to confusion about how to choose the right drug at the right time for the right patient. Additionally, the simultaneous development and progress of immune checkpoint inhibitors (ICIs) has contributed to confusion in the choice of initial treatment options in the first-line setting for patients with dual expression of PD-L1 and driver mutations.

Case Report

Next-generation sequencing (NGS) may clarify the treatment path in NSCLC by aiding assessment of the molecular status of the individual patient, leading to a personalized medicine approach. The following case study and literature review highlight the need for further research.

A 27-year-old student from India pursuing a doctoral degree in economics at the University of Oxford in the United Kingdom developed a progressive cough, shortness of breath, and weight loss in the spring of 2017. He visited his general practitioner at Oxford and was initially treated with a course of antibiotics (azithromycin), without much relief. He continued to lose weight and began to develop cachexia.

After 2 weeks of initial symptoms, a chest radiograph revealed bilateral multiple nodular lesions and a large 3.5 × 4 cm lesion in the right lung. The patient was started on antituberculosis treatment for several weeks with an empirical diagnosis of pulmonary tuberculosis. His condition continued to worsen. After 8 weeks of treatment, he developed hemoptysis and orthopnea. He was hospitalized in early June 2017. A PET/CT scan in June 2017 revealed a fluorodeoxyglucose (FDG)-avid, 40 × 35 mm (standard uptake value, 6) soft-tissue lesion in his right hilar and parahilar regions extending to the right middle lobe; multiple FDG-avid bilateral parenchymal lung nodules; bilateral mediastinal, hilar, and right supraclavicular nodes; and an FDG-avid lesion in the right adrenal gland suggestive of metastatic disease.

At this stage, the patient’s right supraclavicular lymph node was biopsied, and the results revealed meta-static poorly differentiated adenocarcinoma, with 65% PD-L1 expression as determined by an NGS cancer panel (the National Health Service protocol for cancer panel, which includedEGFR,BRAF,TP53,PTEN,PIK3CA,PDGFRA,NRAS, andKRAS). He needed 2 to 3 liters of oxygen continuously.

Given his worsening condition, the patient was airlifted to India to join his parents, with a diagnosis of terminal lung cancer and possible referral for comfort and hospice care. At this juncture, his family reached out to Carolina Blood and Cancer Care in Rock Hill, South Carolina, a Strategic Alliance Partner of Targeted Therapies in Oncology. Kashyap Patel, MD, CEO of Carolina Blood and Cancer Care, Rock Hill, SC, consulted remotely, providing guidance to the patient’s oncologist in India throughout the course of the patient’s treatment.

Pending a second opinion, his primary oncologist in India administered 1 cycle of pemetrexed, carboplatin, and bevacizumab (Avastin). The results of fluorescence in situ hybridization were positive for ALK.

We recommended starting the patient on alectinib (Alecensa) in August 2017.

Within 4 weeks of initiating treatment with alectinib, his performance status improved and he started walking with ambulatory oxygen. After 8 weeks of treatment, the patient started walking 1 mile daily and resumed his studies remotely.

His follow-up PET/CT scan in January 2018 revealed near complete resolution of all liver metastases and adrenal metastases. His lung lesions also resolved.

Discussion

In December 2018, the patient completed the thesis for his doctoral degree and got married. In March 2019, his scans confirmed no evidence of disease. Apart from mild elevation of his liver function, all blood work results were also negative. He currently runs 3 to 4 kilometers every day, works full-time in India, and is enjoying married life. At the last assessment in the summer of 2019, he continued to feel well.

More than 228,000 people in the United States will be given a diagnosis of lung cancer1 in 2019. Lung cancer accounts for 13% of all new cancer cases and almost 25% of all cancer deaths.²It is the leading cause of cancer death regardless of gender or ethnicity. More than half of patients with lung cancer die within 1 year of receiving a diagnosis.³The 5-year survival rate is 19% for all stages, for stage IIIB and IV the rate is 6%.^4,5

Lung cancer is a complex group of disorders associated with a tremendous number of pos-sible molecular aberrations. The growth of many subtypes of lung cancer is driven by complex molecular changes and different abnormal molecular cell signaling pathways, which are often triggered by driver mutations. With these complex molecular subtypes, assessing, treating, and understanding lung cancer necessitates rapid evolution of clinical trials, targeted therapy development, and application of personalized medicine.

Targeted therapies and immuno-oncology (IO) agents play an important role in the treatment of advanced NSCLC. The use of IO agents combined with chemotherapy has revolutionized treatment and outcomes in many patients with advanced NSCLC. However, in patients with coexpression of PD-L1 and other driver mutations (in genes such asEGFR), outcomes with IO agents have been disappointing.6 In particular, KEYNOTE-024 and KEYNOTE-021 excluded patients with sensitizing mutations in theEGFRorALKgene.^7,8The only study of an ICI that included patients withEGFRmutations and PD-L1 expression was stopped prematurely because of lack of efficacy.⁴

It is reasonable to conclude that there is a lack of evidence related to clinical benefit from ICIs as a first-line treatment in patients with metastaticEGFR-mutant NSCLC. Turnaround for PD-L1 testing is quick, but it may take longer to identify other driver mutations. It is prudent to check for all biomarkers prior to rushing to treatment with IO agents. It is reported that 1 of every 3 patients withEGFRmutations may also express PD-L1; hence, it is important to check for all biomarkers prior to initiating immunotherapy. National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing of 4 genes with targetable alterations (ie, with corresponding FDA-approved targeted therapies)—EGFRandBRAFmutations as well asALKandROS1rearrangements—for all patients with NSCLC. Additionally, the NCCN guidelines suggest consideration of testing other “emerging” biomarkers for rarer oncogenic drivers associated with targeted treatments; these include alterations inMET, RET, HER2, NTRK, and KRAS.⁹NCCN also recommends the use of anti-EGFR monotherapy as first-line treatment for patients with EGFR-mutated NSCLC.

In a study of 1203 patients with advanced NSCLC treated in a community setting in 2017 and 2018, only 22% of patients underwent genotyping for all 4 NCCN-recommended genes, with testing rates for individual genes ranging from 29% (BRAF) to 54% (EGFR).10 This study also revealed that only 45% of patients who may have qualified for FDA-approved targeted therapy had evidence of receiving targeted therapy. Furthermore, 37% of patients with a mutation inEGFRorALKand no evidence of progression on the corresponding tyrosine kinase inhibitor received an IO agent, although most of these patients were known to have the targeted alteration at the time of IO agent initiation. There is a significant knowledge gap concerning the need for biomarker testing. Lack of appropriate testing affects over 50% of patients with stage IIIB or IV lung cancer, and their outcome is adversely affected as targeted therapies are not offered despite being clinically indicated.

We present the above case study to emphasize the importance of genetic testing in patients with NSCLC. This case involved the application of clinical and practical experience, as well as the use of biomarker testing and NGS, and it demonstrates how these advanced technologies have increased therapeutic options for patients with NSCLC.

In summary, the field of mutation-directed precision medicine holds the greatest promise for achieving better survival rates while also reducing treatment adverse effects in patients with NSCLC. We are at the cusp of a paradigm shift, with scientific discoveries offering optimism and hope even for patients with stage IV NSCLC, who were once destined for limited survival rates and short life expectancies.

References:

1. Key statistics for lung cancer. American Cancer Society website.cancer.org/content/cancer/en/cancer/lung-cancer/about/key-statistics.html. Updated October 1, 2019. Accessed October 28, 2019.
2. Cancer facts & figures 2019. American Cancer Society website.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed October 31, 2019.
3. How serious is lung cancer? American Lung Association website.bit.ly/36j2e4W. Accessed October 31, 2019.
4. Lung cancer — non–small cell: statistics. Cancer.net website.  bit.ly/2Pz5VNW. Accessed October 31, 2019.
5. Lung Cancer Survival Rates. American Cancer Society website.bit.ly/2WvbU7T. Accessed October 31, 2019.
6. Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.Clin Cancer Res. 2016;22(18):4585-4593. doi: 10.1158/1078-0432.CCR-15-3101.
7. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer.N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.
8. Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 Investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.Lancet Oncol. 2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.
9. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer, version 7. National Comprehensive Cancer Network website.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published August 30, 2019. Accessed October 21, 2019.
10. Gierman HJ, Goldfarb S, Labrador M, et al. Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.J Clin Oncol.2019;37(suppl 15):1585-1585.doi: 10.1200/JCO.2019.37.15_suppl.1585.