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Updated ASCO Recommendations for Advanced NSCLC Include EGFR-, ALK-, ROS1-Guided Precision Options


NEW YORK (GenomeWeb) – The American Society of Clinical Oncology updated its guidelines this week for treating advanced lung cancer by incorporating the latest knowledge around predictive markers and recommending recently approved personalized treatments.

The recommendations for first-, second-, and third-line treatment of patients with Stage IV non-small cell lung cancer come six years after the society's last full guideline update. In the 2009 update, "there wasn't any information on ALK [rearrangements] and the information on EGFR [mutations] information was very preliminary," Gregory Masters, co-chair of the ASCO expert panel that developed and published the guidelines in the Journal of Clinical Oncology, told GenomeWeb. Also, not included in the earlier versions was information on how doctors should treat NSCLC patients with ROS1 rearrangements.

Since the 2011 approval of the first ALK inhibitor Xalkori (crizotinib), the US Food and Drug Administration has green-lighted a number of precision medicine options for advanced NSCLC patients. For example, for patients with ALK rearrangements who stop responding to Xalkori, the FDA last year approved Novartis' Zykadia (ceritinib). ASCO now recommends that in the second-line setting, doctors should offer advanced NSCLC patients with ALK rearrangements chemotherapy or Zykadia.

In the first-line setting, EGFR-mutated, advanced NSCLC patients have three FDA-approved options: Tarceva (erlotinib), Gilotrif (afatinib) and Iressa (gefitinib). ASCO's guidelines recommend these accordingly.

Iressa, for example, re-entered the US market after a 10-year hiatus just this summer. Luckily for sponsor AstraZeneca, it had published data that would support the drug's approval last January, in time for the ASCO panel's literature review cut off. The expert panel scanned the literature between January 2007 and February 2014.

In one case, the research and guidelines have outpaced FDA-approved options. Based on data from a Phase I study, Xalkori sponsor Pfizer is pursuing approval of the drug as a treatment for NSCLC patients with ROS1-positive tumors. Preliminary data from this study were reported two years ago at ASCO's annual meeting.

In April this year, Pfizer announced it had received breakthrough therapy designation from the FDA for Xalkori as a treatment for the ROS1-positive NSCLC. However, ahead of its approval, ASCO now recommends Xalkori as a first-line option for Stage IV NSCLC patients with ROS1 rearrangements.

Given the rapid pace of genomics research in oncology, between the literature review cut-off and the release of the guidelines, there have been new research on additional mutations and advances in the field of immunotherapy that aren't included in the formal recommendations. "What we tried to do was recognize that there were developments," Masters said. "The biggest one is in immunotherapy, with the approval of nivolumab [Bristol-Myers Squibb's Opdivo]."

The guidelines mention that the FDA approved Opdivo for metastatic squamous NSCLC in March, but ASCO experts noted also that the committee is awaiting additional clinical trial data before full incorporation in the guidelines. Moreover, in a section at the end, entitled "future directions," the panel lists ongoing studies on next-generation EGFR inhibitors, anti-PD-1 and anti-PD-L1 immunotherapies, and studies comparing Iressa against Gilotrif.

"This is the nature of treating cancer," Masters said. "The therapies and the data evolve so quickly that even a few months can make a difference." In the next few years, ASCO might provide "a mini update" to provide guidance on immunotherapies, he predicted. Future iterations could also provide more guidance to doctors on which EGFR inhibitor to use in the first-line setting after head-to-head comparisons are performed.

ASCO's guidelines address only advanced lung cancer treatment, Masters emphasized, noting that it's a bit controversial in the field as to precisely when to genomically test cancer patients. "The place where [test results are] clinically applied is recurrent or metastatic disease, so only for patients who have evidence of disease that's no longer going to be treated with surgery or radiation, patients who otherwise would get chemotherapy," he said. "We do that because we might make a change in the treatment if we know they have an activating gene mutation like EGFR, ALK, or ROS1."

Many of the personalized NSCLC drugs recommended by ASCO were launched on the market with FDA-approved companion diagnostics for identifying best responders. However, cancer patients are receiving genomic testing earlier and earlier in their treatment continuum using panel tests that gauge multiple markers at once. Some experts prefer to test patients earlier because so many experience metastases or recurrence. Also, earlier testing could help Stage I or II patients find clinical trials to join. However, Masters noted that the data right now doesn't support using mutation information to guide treatment for early-stage NSCLC patients. 

ASCO simultaneously published an updated policy statement in the same issue of JCO recommending ways in which advanced genomic testing tools may be utilized appropriately for assessing cancer risk.

"We can't work in a vacuum and say that our guidelines cover every possible situation," Masters said, noting that different recommendations can be used to inform practice. "We have to be open minded. We're still learning how we do the testing … Should it be done centrally, on an NGS test … or on individual tests that can be done quicker and more locally?"