Earlier this year, the FDA approved imatinib (Gleevec®) for the treatment of GIST (Gastrointestinal Stromal Tumor) following surgery, based on a study reporting that longer treatment can lead to longer survival among patients at high risk of recurrence.* The 2011 study compared patients who took the drug for one year to those who took it for three years. Patients who took the drug longer were more likely to be alive five years later. It might seem obvious that longer treatment would lead to better survival rates, but earlier studies have not found that to be true. While the drug helps stop recurrence of GIST, it hasn’t been shown to improve long term survival in these patients. This new study is thus important because it seems to contradict earlier findings. However, the study hasn’t been fully analyzed yet. It will be particularly important to confirm these results and to see if tumor markers can predict which patients are most likely to benefit from imatinib. Please read the expanded summary below by an N-of-One expert for further details and analysis of the study's impact.

In work discussed for the first time at the American Society of Clinical Oncology meeting in Chicago in June, 2011, Heikki Joensuu described the results of the combined Scandinavian Sarcoma Group (SSG) / German Sarcoma Group (AIO) study XVII. In a previous study of no treatment after surgery versus 1 year of imatinib, fewer people had their GIST (gastrointestinal stromal tumor) come back if they took imatinib for a year (in comparison to not at all), but there was no difference in survival regardless of whether someone received no extra therapy or 1 year of imatinib.

In the SSG/AIO study, people with GIST believed to be at high risk of recurrence after surgical removal of the original tumor received either 1 or 3 years of imatinib, and then were followed by scans for tumor recurrence. Deaths from the cancer were also recorded. People in whom their GIST came back were allowed to start imatinib and could continue treatment of any kind for as long as they wanted. As expected, there were fewer people who had their tumor come back early if they took 3 years of imatinib, instead of 1 year. However, the surprising finding was that people who took 3 years of imatinib had better overall survival than those who took only 1 year of imatinib. 92% of people with higher risk GISTs were alive at 5 years compared to 82% of those who took only one year of imatinib after surgery.

Researchers were somewhat surprised by this study as it was felt that even 3 years of imatinib was not necessarily expected to prolong survival, based on the older study as well as older data. There are also caveats to this study. We do not know the molecular profile of people who went on the study with respect to issues such as their KIT mutation status, and the like, which could have affected the outcomes. These data are pending. Nonetheless, they support the use of 3 years of imatinib for people who have higher risk of GIST recurrence. The determinants of what defines high risk are in the eye of the doctor and person being treated.

The so-called “Rule of Fives” may help determine who should receive adjuvant imatinib and who should not. This “rule” states that gastric GISTs that are both >5 cm in greatest size (about 2 inches), as well as dividing actively (what is termed as 5 dividing cells (mitoses) per 50 high powered fields), define higher risk GIST patients for whom adjuvant imatinib may be most reasonable. Part two of the rule indicates that for non-gastric GIST, either the large size or high “mitotic rate” is enough to consider the tumor a high risk GIST for therapy.

Many of these data and “rules” that guide treatment may change as we learn more about the imatinib study and also more about the mutation status of the participants. A patient’s molecular profile is likely to be a factor that may determine the potential usefulness of imatinib in this so called “adjuvant” setting for GIST patients.

References:

1. Dr. Robert Maki, Medical Director, Sarcoma Program, and Chief of Pediatric Hematology / Oncology at the Mount Sinai Medical Center, New York, NY

*http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289760.htm

Jeffrey Weber M.D. Ph.D.
Moffitt Cancer Center

The first targeted drug for advanced melanoma -- vemurafenib (Zelboraf) -- has raised considerable hopes because many patients whose cancers have a specific mutation are responding to the drug. That mutation is in a gene called BRAF, and it seems to be a key driver of a subset of melanomas. Thanks to new data from an eagerly anticipated trial of the drug, there’s now more evidence that patients whose cancers have mutated BRAF can benefit from this treatment. Most important, data from this trial and an earlier study suggest the drug not only delays progression of the disease, but actually extends survival. As the review below points out, many important questions remain about how to best use this new therapy, including: Could even further gains come from using other types of drugs prior to vemurafenib therapy? Should vemurafenib be the very first drug patients with the mutant BRAF receive? We now have a lot more data about this important new treatment and many more trials are likely ongoing or to follow.

The recent data published in the New England Journal of Medicine describing the results of the BRIM2 phase II study of the selective BRAF inhibitor vemurafenib in previously treated melanoma patients provides a potent justification for the use of this drug in melanoma patients that have BRAF mutated melanoma¹. While many in the oncology community have focused on the high response rates but short time to progression observed with the use of BRAF inhibitors, the excellent overall survival of 15.9 months in that trial of 132 second line melanoma patients suggests that real survival benefit can be gained from using BRAF inhibitors. The 53% overall response rate is excellent, but the proportion of complete responders (6%) is modest. Due to the early stopping of the randomized BRIM3 study², and subsequent crossover of DTIC patients on the control arm to receive vemurafenib, there may never be a mature comparison in overall survival for that trial, but the front line BRIM3 vemurafenib data may be as favorable as the second line BRIM2 data in overall survival. Admittedly, in both studies, patients could be treated beyond progression, (which occurred in 24% of those on the BRIM2 trial) so the median progression-free survival data of 6.8 months may not reflect the true survival benefit obtained with this drug, which appears to be substantial.

The impressive survival data from the BRIM2 study will provoke further discussion of the notion that BRAF mutated patients without bulky disease or with slow growing melanoma should first go on an immune agent like ipilimumab, high dose IL-2, or even a PD-1 antibody trial in front line in preference to a BRAF inhibitor. While the immune agents may induce a modest proportion of patients to have long-term survival, representing the "tail on the curve ^3,4," as we gain more long-term experience with vemurafenib, similar data may also be seen with that agent. Patients treated past progression, or who have isolated progressing lesions surgically resected, may derive considerable survival benefit from BRAF inhibition. For any patient with BRAF mutated melanoma, there may be a justification for treating with a BRAF inhibitor in front line.

An important question that remains is whether patients that progress after failing a BRAF inhibitor have explosive tumor growth and a rapid downhill course. While the post-progression survival in the BRIM2 and BRIM 3 studies was in the realm of 6-7 months, if the patients stayed on drug past progression, then survival after stopping vemurafenib indeed may have been quite short due to the prolonged time on treatment. The important question of which BRAF mutated patients to treat with a BRAF inhibitor, and whether immune agents should be used first is a critical question that needs an answer.


References:
1. Sosman, J.A, Kim, K.B., Schuchter, L.,Gonzalez, R. et al Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib N Engl J Med 2012;366:707-14.

2. Chapman PB, Hauschild A, Robert C, et al BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16.

3. Hodi FS, O'Day SJ, McDermott DF, Weber RW,et al . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug
19;363(8):711-23

4. Robert C, Thomas L, Bondarenko I, O'Day S,et al . Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26