In helping plan the recent Winter Lung Cancer Conference held last month in Miami (stay tuned for the virtual rebroadcast) I was chatting with faculty member Dr Tom Lynch, who tipped me off that his former team at Mass General was about to publish another blockbuster mutation paper focused on a new translocation called ROS1 (a receptor tyrosine kinase of the insulin receptor family and pronounced “Ross one”).Mass General was about to publish another blockbuster mutation paper The article has now been released electronically by the JCO and details the genetic and clinical characteristics of ROS1-positive tumors and, of particular interest, also describes the amazing case of a 31-year-old man who according to Tom was “on his deathbed” when he was found to have a ROS1 rearrangement. Prior in vitro work, also conducted by the MGH group, had shown ROS1 cells to be sensitive to ALK inhibitors, so the patient was treated with crizotinib as part of a newly launched Phase I trial. Incredibly, he experienced rapid tumor shrinkage with a near complete response and almost a year later he remains on that agent with no evidence of recurrence (click to see the scans).

Not surprisingly, the ROS1 translocation is found mainly in younger never smokers with adenocarcinoma. Like ALK it is detected by FISH assay and has some sequence homology to ALK — perhaps explaining why crizotinib is effective in vitro and in at least one patient. Of particular interest, this rearrangement has also been observed in glioblastomas and cholangiocarcinomas, but the impact of an agent like crizotinib is unknown.

Winter Lung faculty member Dr Pasi Jänne wrote the accompanying JCO editorial and commented during the meeting that oncologists must be on the lookout for nonsmokers who test negative for EGFR and ALK, and while ROS1 is thought to occur in only about 2% of non-small cell cases, this translates to approximately 4,000 people a year in the United States alone. The appearance of yet another potentially “druggable” target in NSCLC should be no surprise considering recent research demonstrating that so-called driver mutations occur in perhaps as many as 60% of pulmonary adenocarcinomas. As a result, we are now approaching or have arrived at a situation very similar to breast cancer with ER, HER2 and the 21-gene Recurrence Score^®, in that the treatment algorithm changes dramatically based on the results of tissue assays. To shed light on how investigators approach the care of individuals with the most common targetable adenocarcinoma mutation (K-ras is more common but there are no effective therapies yet) we asked the 10 Consensus or Controversy faculty members to respond to the following 4 clinical situations that commonly arise in EGFR-positive NSCLC:

1. A young, fit patient with advanced disease and an EGFR tumor mutation
First-line EGFR TKIs have become the standard approach for these patients, underscoring the need to rapidly access adequate (core) tissue in order to identify them. Based on discussion at Winter Lung, many investigators are already following this pattern for patients with ALK translocations, opting for a first-line TKI rather than chemo even though the pivotal trial was conducted in the second-line setting. It will be interesting to see how patients with ROS1 tumors are managed once physicians begin identifying them regularly.

2. An older, fit patient with advanced disease and an EGFR tumor mutation
We presented an 82-year-old patient, and maybe what’s important here is not that an EGFR TKI is indicated but rather that all patients regardless of age should be considered for biopsy and mutation testing to individualize treatment rather than simply receiving an empiric TKI.

3. A patient with an EGFR tumor mutation and prolonged response to an EGFR TKI but now with slow progression
A lot of discussion is going on in many tumor types and with many biologic treatments about the issue of continuation of a targeted treatment on disease progression. Interestingly, in this situation 7 of the 10 faculty members would consider continuing the EGFR TKI particularly if the patient were stable and asymptomatic.

All eyes are on continuing research with an intriguing “total EGFR” blockade strategy reported last year at ASCO in patients with progressive disease on a reversible EGFR TKI, combining the irreversible EGFR TKI afatinib and the anti-EGFR antibody cetuximab. The impressive waterfall plot from this Phase II effort illustrates that almost all patients had some tumor shrinkage, and while it is not yet clear whether afatinib will turn out to be more effective as monotherapy than less selective TKIs, we do know that the combination strategy does not work when using a reversible EGFR TKI (erlotinib) with cetuximab. Since afatinib is not yet approved, this strategy can therefore only be employed as part of a trial.

4. A patient with advanced disease who is started on a platinum doublet and bevacizumab but after 3 courses is found to have an EGFR tumor mutation
No definitive trial data address this not-uncommon situation. Most of the faculty (6 of 10) would finish 4 or 6 cycles of chemo first and then opt for maintenance erlotinib, but a number would stop chemo/bev and switch to the TKI.

 

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