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Targeted Therapies Moving into First-Line Therapy Underscore Need for Baseline Molecular Testing of Lung Cancers

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 - 39th Congress of the European Society for Medical Oncology (ESMO)

Madrid, Spain / September 26-30, 2014

Madrid - Guidelines issued by ESMO just prior to the annual Congress call for routine molecular testing at the time of diagnosis in all patients with non-small cell lung cancer (NSCLC). New phase 3 data on ALK-positive (ALK+) NSCLC presented at the Congress strengthen that recommendation. Based on data reviewed and presented at the Congress, targeted therapies appear to be the optimal first-, second-, and possibly third-line treatments for individuals with ALK+ NSCLC. The value of targeting ALK was found to be at least as great as that previously demonstrated in NSCLC with driver mutations in EGFR. Targeted therapies for other oncogenes, such as ROS1 and MET, suggest that treatments will eventually be selected for all or most NSCLC on the basis of molecular subtypes. An evolution that is advancing rapidly across many cancer types, the value of the molecular profiling in order to select targeted therapy in NSCLC has now reached an advanced stage of practical application.

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

A series of studies evaluating treatments for NSCLC positive for rearrangements of the anaplastic lymphoma kinase (ALK) gene have reinforced the recently issued ESMO guideline that calls for molecular profiling of NSCLC at the time of diagnosis (Kerr et al. Ann Oncol 2014;25:1681-90). In these studies, including a phase 3 trial that establishes a new standard for first-line treatment, there has been a large advantage for targeted therapies over conventional chemotherapy for improvement in clinically meaningful endpoints, such as progression-free survival (PFS).

“When we know the mutation driver and we have a targeted therapy, we are provided with a more rational approach to disease control,” reported Dr. Tony Mok, Department of Clinical Oncology, Chinese University, Hong Kong, China. Although he was speaking specifically about targeted therapies for ALK+ NSCLC, Dr. Mok’s comments were relevant to the reorientation toward individualized NSCLC therapy.

At ESMO Congress, attention was focused on ALK+ NSCLC with the phase 3 PROFILE 1014 trial. In that study, the small molecular tyrosine kinase inhibitor (TKI) crizotinib provided a highly significant advantage (P<0.0001) over pemetrexed-based platinum chemotherapy for the primary endpoint of PFS in first-line treatment of advanced disease. The data were considered practice changing.

First Line Therapy in ALK+ NSCLC

“The PROFILE 1014 trial now establishes the efficacy of crizotinib as first-line therapy in advanced ALK+ lung cancer,” reported Dr. Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston. The ESMO-invited discussant for this study, Dr. Shaw noted that crizotinib is already a standard for second-line therapy, but this trial moves the therapy forward.

In PROFILE 1014, presented by Dr. Benjamin Solomon, Peter MacCallum Cancer Centre, Melbourne, Australia, 343 previously untreated patients with advanced ALK+ NSCLC were randomized to oral crizotinib or to pemetrexed plus either cisplatin or carboplatin administered intravenously every three weeks. Crossovers from one treatment to the other were permitted at the time of disease progression established by independent review.

On the primary endpoint of PFS, the hazard ratio (HR) favoring crizotinib was 0.45 (95% CI: 0.35 – 0.60; P<0.0001), providing the targeted therapy with a 55% relative advantage over chemotherapy. The median PFS was extended from 7.0 months in the chemotherapy group to 10.9 months on crizotinib. The time to response (6.1 vs. 12.1 weeks) and duration of response (49 vs. 22.9 weeks) also favored crizotinib.

Adverse Events Acceptable

Relative to chemotherapy, visual disturbances (71% vs. 9%) were the most common type of toxicity on crizotinib. These ranged from light trails in the peripheral vision to blurring but were generally mild in intensity. Other adverse events more common on crizotinib included diarrhea (61% vs. 9%), and edema (49% vs. 12%). On chemotherapy, there was a greater relative frequency of fatigue (38% vs. 29%), neutropenia (30% vs. 21%), and stomatitis (21% vs. 14%). Grade 3 or higher events on either therapy were relatively infrequent, and Dr. Solomon characterized the overall safety and tolerability in the two study arms as “acceptable.”

The inclusion of patients with brain metastases in PROFILE 1014 was a reflection of the common presentation of advanced NSCLC. Although only 23% of the participants had brain metastases, limiting the power of the comparison, there was a trend for a time-to-progression (TTP) advantage for the crizotinib arm in this subgroup. This activity was an area of focus in the remarks by Dr. Shaw, who also discussed a study on an alternative ALK inhibitor, alectinib, which was presented just prior to the PROFILE 1014 results.

“These data suggest modest but real anti-tumor activity for crizotinib in the CNS,” according to Dr. Shaw, who pointed to other data that also suggested penetration of this drug into the central nervous system, the most common site of NSCLC relapse.

Sequential ALK Inhibitors Possible

However, brain metastases after a prior ALK inhibitor do not preclude targeting the ALK pathway in second-line therapy, according to results of the alectinib study. Presented immediately prior to PROFILE 1014 and also discussed by Dr. Shaw, the study included 35 Japanese patients with ALK+ NSCLC and brain metastases. All received oral alectinib. Most had been previously treated with crizotinib.

After a median follow-up of 10.2 months, the median PFS of patients on alectinib in this study has not been reached, according to the presenting author, Dr. Takashi Seto, National Kyushu Cancer Centre, Fukuoka, Japan. Consistent with a high intracranial drug penetration in animal models, alectinib produced an overall response rate (ORR) of 58.3%. In the subgroup of 23 patients who had progressed on crizotinib, the ORR was 50%.

Suggesting that these high rates of response after crizotinib are consistent with other “next generation” ALK inhibitors that have been evaluated in ALK+ NSCLC, such as ceritinib and AP26113, Dr. Shaw outlined a treatment strategy for ALK+ NSCLC that she believes is now emerging.

Emerging Order of Therapies

“Based on these data, crizotinib should now be used as first-line therapy in newly diagnosed ALK+ NSCLC, but when patients relapse and a change is required, switching to a next generation inhibitor like alectinib or ceritinib, is reasonably supported by multiple single arm studies,” Dr. Shaw said. She considers pemetrexed “a reasonable option if a next generation TKI is not appropriate,” but she also suggested that a trial of a third-line ALK inhibitor might be reasonable even after failure of two previous ALK inhibitors.

The differences in ALK inhibitors may explain why one agent demonstrates activity after another fails. Crizotinib, for example, targets ALK, MET, and ROS1 tyrosine kinases. Ceritinib also targets ALK and ROS1 as well as the insulin-like growth factor 1 receptor. Alectinib appears to exert stronger inhibition of ALK than either crizotinib or ceritinib but does not target ROS1. Of the mutation drivers that have been identified, ALK, representing about 3% to 7% of NSCLC is observed less frequently than EGFR or KRAS mutations, but is more common than such driver mutations as BRAF, MET, and ROS1.

Therapies that target multiple oncogenes might show activity against more than one molecular subtype of NSCLC. In data presented by Dr. Shaw as a poster, crizotinib was evaluated in a series of 50 patients with ROS1-rearranged NSCLC. Patients with stable, previously treated or asymptomatic brain metastases were eligible. In this group, the objective response rate was 72% with a mean time to response of 7.9 weeks and a median PFS of 19.2 months.

“Crizotinib demonstrated potent antitumor activity in this population, suggesting that ROS1 rearrangement defines a second molecular subset of NSCLC for which this TKI may provide sustained disease control,” Dr. Shaw reported.

Although this was a small study and patients with ROS1 rearrangements represent only about 1% of NSCLC, these data further reinforce the evidence that molecular profiling is now essential for guiding therapeutic choices. As treatments evolve with more clinical data comparing options, the role of molecular profiling will gain further importance as part of the standard of care in NSCLC.


Data presented on ALK+ NSCLC at the 2014 ESMO Congress have provided timely reinforcement of the recently released ESMO guidelines that recommend molecular profiling at the time of diagnosis in all patients with NSCLC. Although targeted therapies have yet to be developed for many driver mutations, the molecular subtype can lead a growing proportion of patients to targeted therapies that offer high rates of response and, in some cases, a lower risk of toxicity than conventional cytotoxic chemotherapies. The most recent data emphasize the critical role played by individualization of targeted therapies in NSCLC management. 

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