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The Right Drug at the Right Time in the Right Patient: Reflex Biomarker Testing in NSCLC Should Become a National Strategy

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Lung Cancer Summit 2015

Toronto, Ontario / October 30, 2015

Toronto - Recent guidelines from the American Society of Clinical Oncologists state that systemic therapy for advanced non-squamous non-small cell lung cancer (NSCLC) should start with knowledge of a patient’s biomarker status followed by either chemotherapy or a targeted therapy directed against a specific mutation. Barriers to establishing biomarker status include having the oncologist order the test at the time of first assessment which means that treatment is often delayed or a potentially inappropriate treatment is initiated in the absence of test results. Having the pathologist order biomarker testing on diagnosis of NSCLC promises to override lengthy delays and early findings indicate that reflex biomarker testing should become the standard of care in the management of NSCLC.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Time for Molecular Testing is Now

The time for molecular testing has arrived for patients with non-squamous, non-small cell lung cancer (NSCLC) and pathologists should be the ones to request biomarker testing once NSCLC is diagnosed so that oncologists can be guided by biomarker results when selecting first-line treatment for their patients.

“It’s very clear that biomarker status drives first-line systemic therapy recommendations, yet the discovery of actionable targets in advanced NSCLC has significantly outpaced implementation in day-to-day clinical practice,” Dr. Parneet Cheema, Medical Oncologist, Sunnybrook Odette Cancer Centre, Toronto, Ontario told delegates at the Lung Cancer Summit here.

Specifically, patients need to be tested for the presence of epidermal growth factor receptor (EGFR) status as well as ALK rearrangement as both of these mutations can be effectively targeted with treatments directed against each of these respective mutations, she added. In fact, the majority of patients with NSCLC have a driver mutation that is identifiable and possibly a target for an approved therapy or a clinical trial. More biomarkers are also coming down the pipeline and they, too, will affect selection of first-line therapy, “so it’s really important to get these markers done early,” she emphasized.

The problem is that there are real barriers to getting biomarker status assessed in a timely manner. In a survey of 41 medical oncologists in Canada, 29% of a group of NSCLC patients had no EGFR testing at all and EGFR status was unknown in 45% of patients when oncologists had to decide on which first-line therapy to choose. “Waiting for biomarker results is a major barrier to implementing personalized medicine in advanced NSCLC,” Dr. Cheema affirmed.

This is partially because the majority of patients with NSCLC present with advanced disease—they come into the clinic symptomatic with pleural effusions, they have painful bone metastases—and oncologists are faced with either having to wait for biomarker results or bite the bullet and treat patients immediately because they fear patients will deteriorate clinically.

There is also the real problem of not having sufficient tissue to test because fine needle aspiration and core biopsies provide little material with which pathologists can work. To improve biomarker testing rates and time to biomarker-guided treatment initiation, multiple centres across Ontario including Sunnybrook have instituted “reflex” testing.

Reflex Testing

“Reflex testing is when pathologists request EGFR and ALK status at the time of diagnosis of NSCLC irrespective of stage, so patients at all stages of the disease get tested for these biomarkers,” Dr. Cheema said. In their own advanced patients, biomarker testing has reached almost 100% for EGFR status and 89% for ALK rearrangement. Knowing a patient’s biomarker status at the time of first consultation has reduced the time to treatment from 29 days when EGFR/ALK status is unknown down to 16 days when biomarker status is known.

Reflex testing has also decreased the rate of unsuccessful tests due to inconclusive results or insufficient or inappropriate tissue being sent for testing to minimal levels. “When we exclude patients who were intentionally delayed for radiation therapy time to optimal first-line systemic therapy has also improved by 12 days,” Dr. Cheema said. “And I think we need a national strategy for equal and timely access to molecular testing in NSCLC.”

From a pathologist’s perspective, advantages of reflex testing include having more complete knowledge of the pathology of a patient’s tumour which includes molecular features of the tumour. Reflex testing should also improve overall diagnostic efficiency by avoiding the need to revisit the sample after initial diagnostic work-up, as Dr. Ming-Sound Tsao, Professor of Laboratory Medicine and Pathology, University of Toronto, suggested.

Genotype-Directed Therapy

The fact that genotype-directed therapy improves survival in metastatic lung adenocarcinoma is clearly supported by the literature. In a lung cancer consortium study involving 14 US sites, median survival was 3.5 years among patients who had a driver mutation and who received the appropriate targeted therapy vs 2.4 years for patients with a driver mutation but who did not receive targeted therapy, virtually the same as a median survival of 2.1 years for patients who had no driver mutation. One example of a clinically meaningful improvement in progression-free survival (PFS) in ALK+ NSCLC patients was demonstrated in the PROFILE 1014 trial.

In the trial, PFS in patients randomized to the ALK inhibitor, crizotinib, was 55% longer at a hazard ratio of 0.45 compared to patients treated with pemetrexed plus either cisplatin or carboplatin: 10.9 months in the crizotinib arm compared with 7 months in the chemotherapy arm. Time to response at 6.1 weeks for the ALK inhibitor arm compared with 12.1 weeks for the chemotherapy arm as well as duration of response at 49 weeks compared with 22.9 weeks also favoured crizotinib.

“We are not expecting to see overall survival differences, we are used to this from the tyrosine kinase inhibitor story from EGFR NSCLC,” Dr. Jeffrey Rothenstein, Durham Regional Cancer Centre, Ontario said. “But importantly, quality of life is improved when you use targeted therapy in the first-line setting so these are all good reasons for using a targeted ALK inhibitor first-line.” Dr. Barbara Melosky, clinical assistant professor of medical oncology, University of British Columbia, Vancouver, reminded delegates that while ALK rearrangement is a rare mutation, “these patients live many years and we have multiple patients with ALK in our clinics.”

Typically, patients are never or light smokers and ALK+ disease tends to occur in young patients. Compared to patients with EGFR NSCLC, patients with ALK+ NSCLC have more organ involvement and their tumours are more aggressive than EGFR tumours. “About one-quarter of our patients with ALK present with brain metastases,” Dr. Melosky added. “So even if patients are asymptomatic, it’s important to look for brain metastases when we start them on treatment and watch their brain throughout treatment.”

Patients with ALK+ NSCLC do progress and when they do, they can progress either systemically or into the brain. While the percentage of patients in the pivotal PROFILE 1014 study who had brain metastases was limited, there was a trend for an advantage in time to progression in the crizotinib arm in this subgroup of patients compared to the chemotherapy arm. Once patients progress on crizotinib, a retrospective analysis of pivotal trials showed that patients who continue to receive treatment with the ALK inhibitor have continued clinical benefit, with a median overall survival of 16.4 months for those who stayed on treatment vs 3.9 months for those who did not.

There are also now second-generation ALK inhibitors that can be used following the development of resistance to crizotinib, Dr. Melosky observed. Two such second-generation agents include ceritinib and alectinib. Ceritinib is now standard of care in the US following progression on crizotinib. Response rates to ceritinib in ALK inhibitor native patients are in the range of 60% although response rates and PFS curves are less robust in heavily pretreated patients.

“However, ceritinib is a harder drug than crizotinib,” Dr. Melosky observed, “and many patients in ceritinib trials required a dose reduction and grade 3 and 4 adverse events were more common than they were in crizotinib trials.” The good news, she added, is that multiple agents are now being tested for ALK+ patients.

“I’m an optimist,” Dr. Melosky said, “and I predict ALK+NSCLC is going to become a chronic disease because we will have multiple lines of ALK inhibitors.”


Targeted therapies for EGFR+ and ALK+ NSCLC are growing in number, the hope being that each successive generation of EGFR and ALK inhibitors will be able to overcome resistance mutations when they occur. Armed with a burgeoning choice of agents, it is imperative that oncologists know a patient’s mutation status on initiation of treatment as any driver mutations that are present may be directly targeted with new and existing therapies. Reflex testing ordered by the pathologist promises to speed up the process and bring the best treatment forward more promptly to the patient.  


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