The following is a recap of the presentations and posters from the CTOS conference held in Hawaii, with commentary by David Josephy.
Dr. Michael Heinrich, David Josephy and Norman Scherzer
CTOS 2017 Presentations Related to GIST
There was one platform session on GIST at CTOS. The first two talks were updates on the trials of the Blueprint and Deciphera drugs for GIST, exciting developments that will be presented separately by LifeRaft and others. The third talk was “KIT MUTATION:ZYGOSITY IMPACTS TKI SENSITIVITY IN GIST” by a group of authors including Jonathan Fletcher at Harvard Medical School (senior author) and author Armelle Dufresne at Centre Leon Berard, Lyon, France. The Dufresne study is an in vitro (tissue culture) study of imatinib resistance mechanisms in cultured GIST cells. They found that homozygous secondary imatinib-resistance mutations confer greater drug-resistance than heterozygous mutations. Each cell has (normally) two copies of each gene, including the KIT gene. Mutations (“primary mutations”) in KIT drive most GISTs. When additional (“secondary”) mutations arise in one of the KIT genes, they can make the cells more resistant to imatinib. The concept of the paper was that the second copy of the gene – not carrying the resistance mutation – can maintain some imatinib sensitivity in the cells. But genetic mechanisms exist whereby the “bad” (secondary resistance) copy of KIT can drive out the “good copy”. This leads to “homozygosity”, i.e., two “bad” genes. The paper showed that such cells have greater drug resistance. This is a technical paper on the molecular genetics of KIT mutations, but it suggests important implications for treatment of progressive GIST. The authors conclude that “there are two reasons that GIST patients should continue to receive KIT/PDGFRA-inhibitors [such as imatinib] after clinical progression. First, as is well known, most GIST patients with secondary TKI-resistance have some burden of disease with only the primary TKI-sensitive mutation. Second, some progressing GISTs have homozygous primary mutations and heterozygous secondary resistance mutations, in which a subset of the oncogenic kinase dimers remain TKI-sensitive.”
David’s view: I think that these are important findings that may change the way we look at the mechanisms of evolution of drug-resistant GIST clones.
CTOS 2017 Posters Related to GIST
CTOS posters #59-75 were about GIST. Here are brief summaries and my personal opinions about these posters.
A PHASE 1 PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) STUDY OF PLX9486, A NOVEL KIT INHIBITOR WITH POTENT ACTIVITY AGAINST EXON 17/18 ACTIVATION LOOP MUTATIONS IN PATIENTS WITH GIST
The authors include Jonathan Trent, University of Miami Sylvester Cancer Center; Bill Tap, Memorial Sloan Kettering, New York; scientists at Plexxikon; and others.
This is an early clinical trial of a new drug, PLX9486, which has activity against some imatinib-resistant KIT mutations. The aim was to determine the maximum tolerated dose (MTD) of the drug in a dose escalation study. Circulating tumor DNA (ctDNA) was also obtained from the patients. Common adverse events included nausea, diarrhea, fatigue, peripheral edema, and anemia (as with many TKI drugs). The authors concluded that “PLX9486 … demonstrates a favorable safety profile. … The recommended phase 2 dose is 1000 mg QD [i.e., daily]. Expansion cohorts in GIST are planned as are combinations with sunitinib and pexidartinib which have complementary activity against KIT resistance mutations.”
David’s view: This is a promising beginning for clinical trials of a new agent for imatinib-resistant GIST.
TRIAL IN PROGRESS: A RANDOMIZED PHASE 2 STUDY OF NIVOLUMAB MONOTHERAPY VERSUS NIVOLUMAB COMBINED WITH IPILIMUMAB IN PATIENTS WITH METASTATIC OR UNRESECTABLE GIST
This was presented by doctors at Hematology Oncology, UCLA, and scientists at Bristol Myers Squibb.
It reports a randomized Phase 2 trial to evaluate response in patients with advanced GIST treated with nivolumab or nivolumab + ipilimumab. Nivolumab (Opdivo) is an anti-PD-1 monoclonal antibody, a bio-therapeutic “checkpoint inhibitor”, that stimulates the immune system to attack the cancer. It is being used in melanoma and other cancers. Ipilimumab (Yervoy) is also a monoclonal antibody used in melanoma that activates the immune system, targeting CTLA-4. The poster was an update; the clinical trial is in its early stages, accruing patients.
David’s view: Monoclonal antibodies for immunotherapy have not had much success in GIST, so the odds are not great for this combination being a big improvement over the individual agents.
GENOTYPE AND RISK OF TUMOR RUPTURE IN GIST
The authors are at the Department of Pathology, Oslo University Hospital, Norway.
They did mutational testing on a series of GIST patients and looked to see whether any particular mutational type correlated with tumor rupture. They saw a small effect whereby KIT exon 11 deletions involving codon 557 and 558 were at increased risk of rupture.
David’s view: Small sample, small effect, and no strong rationale. I doubt that this result will be validated.
RE-CHALLENGE IN ADVANCED GIST PROGRESSING TO IMATINIB, SUNITINIB AND REGORAFENIB: AN ITALIAN SURVEY
The authors are a group of Italian GIST specialists, with Dr. Dei Tos as senior author.
The research is a retrospective analysis of data from 71 metastatic GIST patients treated with imatinib or sunitinib reintroduction after progression. The mutation status of each patient was analyzed. The idea of re-challenge with first- or second-line agents in progressive GIST is being looked at in many institutions. The group concluded that, at least in KIT exon 11 mutated patients, re-challenge significantly prolonged Overall Survival, “confirm[ing] that the re-challenge of imatinib or sunitinib is a reasonable option in advanced GIST patients after failure of previous treatments.”
David’s view: Further support for the “re-challenge”: approach in advanced GIST.
DUAL INHIBITION OF AKT AND KIT IS SYNERGISTIC IN GIST
Authors at Fox Chase Cancer Center, Philadelphia, including Dr. von Mehren, and researchers at ArQule Inc, in Massachusetts.
“We performed in vitro and in vivo experiments to assess the potential benefit of combining imatinib with an ArQule AKT inhibitor, ARQ 092.” AKT is a mediator of a major signal transduction pathway for cell survival.
The idea is to combine inhibition of KIT signaling with inhibition of AKT signaling. The studies are done on imatinib-sensitive and imatinib-resistant GIST cell lines, treating with drugs and then measuring cell killing, and they are also treating mouse xenografts. They found that “combination therapy demonstrated significantly greater efficacy … in the imatinib-sensitive xenograft model. In vivo studies in imatinib-resistant models are ongoing and data will be reported in November.” and that “These results provide justification for evaluating this combination in GIST patients.”
David’s view: “Double-whammy” drug combos like this have not worked as well in GIST as had been hoped, but the approach makes scientific sense and deserves to be pursued.
BASELINE BLOOD NEUTROPHIL-TO-LYMPHOCYTE RATIO IS ASSOCIATED WITH LONG-TERM OUTCOMES OF GIST TREATED WITH IMATINIB AND SUNITINIB
Authors are Dr. Rutkowski and others at the Oncology Center in Warsaw, Poland.
The research looked at a white blood cell parameter, the neutrophil-to-lymphocyte ratio (N/L), as a possible predictive or prognostic marker in advanced GIST. They concluded that monitoring this parameter “may be helpful for assessment of disease progression or response.”
David’s view: Unlikely that this approach will have as much impact as other biomarkers, especially ctDNA.
SURGICAL AND MEDICAL MANAGEMENT OF SMALL BOWEL GISTs: A REPORT OF THE DUTCH GIST REGISTRY
“Patients with GIST … treated in one of the five participating centers are registered in the Dutch GIST registry (Jan 2009-ongoing).” The researchers analyzed mutational status, treatment, and outcomes.
David’s view: No major surprises, but this is the sort of pro-active testing and analysis of results that we would like to see happening everywhere.
SURVIVAL OUTCOMES IN METASTATIC GIST PATIENTS HAVE BEEN DRAMATICALLY IMPROVED BY TYROSINE KINASE INHIBITORS: REAL WORLD DATA FROM MULTIPLE INSTITUTIONS
The authors are at BC Cancer Agency in Vancouver, B.C., Canada; including Dr Charles Blanke, now at OHSU Knight Cancer Institute, Portland, Oregon.
Somewhat like the preceding poster, this is an analysis of “real-world” data on treatment and outcome in GIST, looking at data on 657 patients with advanced GIST treated at any of the five tertiary cancer centres in B.C., 1997-2013, a period during which treatment options increased dramatically. Survival outcomes “have improved significantly since the introduction of [imatinib] 15 years ago”.
David’s view: Again, no surprises, but we need this sort of data gathering and analysis to understand “how we are doing” and possibly to identify any system failures with regard to diagnosis and treatment.
THE NFC CLONE, A NEUROFIBROMIN C TERMINUS- SPECIFIC ANTIBODY, IS A VALUABLE TOOL FOR THE IDENTIFICATION OF NF1-INACTIVATED GISTS
The authors are a large group of pathologists in Germany and Italy, including Dr. Dei Tos, Treviso General Hospital, as senior author.
The NF1 gene is mutated in some GISTs, but, for technical reasons (e.g., large size of the gene and wide spectrum of mutations), “analysis of NF1 gene status is still problematic for most laboratories”. So, the authors looked at whether a “recently developed neurofibromin-specific antibody (NFC)” would be useful in the pathology lab, so that NF1 inactivation could be measured at the protein, rather than DNA, level. They report that the antibody staining approach could indeed be useful “for the identification of NF1-inactivated GISTs, thus serving as a surrogate for molecular analysis.”
David’s view: Could be a useful new tool for the pathology lab., for identifying NF1-mutant GIST.
INHIBITION OF AUTOPHAGY SENSITIZES GIST CELLS TO TKI/BCL-2 INHIBITORS-INDUCED APOPTOSIS
- Zhang, in Qingdao, China et al.; senior author is Jon Trent, Sylvester Comprehensive Cancer Center, Miami.
This is a tissue-culture study looking at killing GIST cells with double or triple drug combinations, especially signal-transduction inhibitors that induced apoptosis (programmed cell death).
David’s view: Valuable in vitro studies that might indeed, as the authors claim, “provide a rationale for the clinical evaluation of these drug combinations in GISTs treatment.” Still a long way to go before clinical effectiveness, however.
EARLY RESPONSE EVALUATION BY 18F-FDG-PET INFLUENCES MANAGEMENT IN GIST PATIENTS TREATED WITH NEO-ADJUVANT INTENT
Authors are oncologists at several Dutch hospitals. They analyzed the value of doing PET scanning in GIST: does it affect doctors’ treatment decisions? “All patients in the Dutch GIST Registry treated with imatinib with neo-adjuvant intent were identified.” They concluded that “early response evaluation by FDG-PET often leads to change in management” for patients with non-KIT exon 11 mutated GISTs but not for those with KIT exon 11 mutations.
David’s view: Still rather small numbers, so this needs to be followed up with larger studies; PET is still not a standard imaging modality in GIST and it is only available in some well-equipped centers.
THE OUTCOMES OF TREATMENT OF PATIENTS WITH ADVANCED GIST IN ELDERLY
This is a poster from oncologists in Poland, with GIST specialist Dr. Peter Rutkowski (who has presented talks at New Horizons) as first author. They note that “there are limited data on treatment outcomes of elderly patients …[who are also] under-represented in clinical trials. The aim of the study was to analyze the results of treatment of patients with advanced GIST in the elderly …” They concluded that “current therapy of advanced GIST … can allow [elderly patients] to achieve … similar … outcomes as younger patients, but it demands the close cooperation of experienced oncologist with patients for dose modifications and side effects management.”
David’s view: An important reminder that elderly GIST patients deserve – and benefit from – expert clinical practice as much as younger patients.
PROGNOSTIC VALUE OF SERUM INFLAMMATION MARKERS IN GIST
- Cananzi et al., Surgical Oncology Unit, Humanitas Clinical and Research Hospital, Milan, Italy.
“The aim … was to investigate the value of preoperative serum inflammation markers in determining the prognosis of GISTs.” Inflammation was assessed by multiple measurements of white blood cell counts, such as neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio, etc. Statistical correlations with disease-free survival (DFS) were analyzed. They concluded that specific serum inflammation indices “are independent prognostic factors for DFS in GIST” and that their inclusion “in the clinical management of GISTs should be considered, since they may improve the accuracy of risk estimation”.
David’s view: The correlations need to be tested in further studies; even if confirmed, unlikely to have much clinical impact.
PATIENT REPORTED TREATMENT RESPONSES IN KNOWN/LIKELY SDH-DEFICIENT GISTS: ANALYSIS OF THE LIFE RAFT GROUP OBSERVATIONAL REGISTRY
This is the poster from the LRG – nice to see it displayed alongside the other posters; I will leave it to Jerry Call to discuss the study and its findings.
The Life Raft Group recently presented a poster at the 2017 CTOS (Connective Tissue Oncology Society) meeting in Hawaii. The subject of the poster was essentially; “What do we know about response of SDH-deficient GIST to drugs”? The question presents several challenges. First, most GIST patients do not get mutational testing, and even among those that do, testing usually stops if a mutation is not found in the KIT or PDGFRA gene. This means that the vast majority of SDH-deficient patients remain un-identified; even in a proactive patient group like the Life Raft Group.
The mutational testing rate has risen significantly over the years and approximately 70% to 75% of patients recently diagnosed are reporting mutational testing to the registry. However nearly 50% of living registry patients still don’t know, or haven’t reported their mutation type to the registry.
As reported in the LRG poster, 117 patients reported some type of mutation other than KIT or PDGFRA. In the past, these would all be grouped as “wildtype”. Wildtype basically meant, “we tested KIT and PDGFRA” and they were normal, but we still think you have GIST. Our understanding of this group today had improved dramatically and testing can identify the molecular defect responsible for the vast majority of these GISTs.
Of the 117 patients in the registry with mutational testing, but without KIT or PDGFRA mutations, 98 remain “unclassified” wildtype and only 28 could be positively identified as SDH-deficient. SDH-deficient patients can be classified either with a mutational test that reveals a SHDx mutation, or a negative SDH-stain.
SDH-deficient GIST is thought to respond poorly to current drugs, so 28 patients is not enough to really get a good idea of drug response. In order to increase numbers, we also considered histories of patients “likely to be SDH-deficient”. We did this by looking at criteria that predicted SDH-deficiency, both within the LRG registry as well as previously published criteria and found 58 patients with “likely SDH-deficient” GIST. We then tested how similar they were to known SDH-deficient GIST with respect to response to imatinib and overall survival. The likely SDH-deficient group were very similar to the known SDH-deficient group, which allowed us to combine the two groups. This tripled the number of cases available to look at drug responses, at the expense of possibly including some non-SDH-deficient patients in the group.
Even with triple the number of treatment cases to look at; the total number of cases was still small, especially considering the responses to drugs are poorer than the typical adult type GISTs. Given the significant limitations of the study, the results were not definitive. However, there were hints of activity in two areas; patients reported shrinkage more often with sunitinib (Sutent) than with other drugs, and, in very small numbers, patients seemed to stay on regorafenib longer than other drugs.
Our conclusions were that GIST patients need to have mutational testing and in cases negative for KIT and PDGFRA mutations, testing must continue to identify SDH-deficient GIST and other subtypes. In addition, better treatments are needed for SDH-deficient GIST. – Jerry Call
REMARKABLE EFFECTS OF IMATINIB IN A FAMILY WITH YOUNG ONSET GISTs AND CUTANEOUS HYPER- PIGMENTATION ASSOCIATED WITH A GERMLINE KIT-TRP557ARG MUTATION: CASE REPORT AND LITERATURE OVERVIEW
Authors are medical oncologists in Amsterdam.
Germline KIT mutations in GIST are extremely rare. This is a very interesting case report about one affected family, and an overview of the literature on germline KIT mutations was also prepared. A 52-year old patient with presented with “multiple GISTs throughout the GI tract and cutaneous hyperpigmentation”. A previously unknown germline mutation in KIT (exon 11) was found. The patient received matinib and “showed long-term regression of the GISTs … Remarkably, the hyperpigmentation of the skin also diminished”. “Genetic screening of the family revealed the same mutation in two daughters, both with similar cutaneous hyperpigmentation. One daughter, aged 23, was diagnosed with multiple small intestine GISTs … She was treated with adjuvant imatinib. The authors conclude that “Imatinib treatment in GIST patients harboring a germline KIT mutation shows favorable and long- term responses in both the tumor and the hyperpigmentation.”
David’s view: Inherited GIST is so rare that each new instance leads to interesting new evidence. Here, imatinib treatment proved to be very effective.
Poster 074 #2791377
BASELINE RESULTS AND CENTRAL PATHOLOGY OF THE PROSPECTIVE REGISTRY STUDY OF HIGH RISK GIST AFTER COMPLETE RESECTION (STAR REGISTRY) IN JAPAN
Authors are a large group of Japanese oncologists, including Dr. Hirota, one of the discoverers of the role of KIT in GIST.
This is another “real-world” examination of pathologiy/diagnosis and adjuvant therapy use, in this case, in Japan.
“Between Dec. 2012 and Dec. 2015, 534 patients with histologically-confirmed high-risk GIST based on the Joensuu classification in the local site were registered … and analyzed. In the central pathology, H&E, immunohistochemistry, and genotyping were done.” The authors emphasized the continuing problems with pathology done at local hospitals. “19 tumors (3.6%) … were diagnosed as non-GIST … in the central pathology”; in plain words, the local pathology work was wrong. The authors conclude that “pathological diagnosis by sarcoma pathologists and adjuvant therapy based on the guidelines are still required to improve in real-world clinical practice”.
David’s view: If a substantial number of pathology errors are still happening in Japan, which is basically where modern GIST medicine started, what does that say about other countries??
Poster 075 #2792679
LONGITUDINAL FOLLOW UP OF CONTEMPORARY TREATMENT RESULTS IN ADVANCED GIST – A SINGLE CENTRE EXPERIENCE
From oncologists at Sahlgrenska University Hospital in Sweden.
This is another real-world study, a “detailed analysis of clinical data for a contemporary cohort of 31 patients with palliative TKI treatment due to … inoperable or recurrent GIST.” “Retrospective analysis of 31 patients [with] advanced GIST at … Sahlgrenska University Hospital from 2012 to 2016.” The conclusion is that the results with TKI therapy in Sweden are comparable to experience elsewhere.
David’s view: Another worthwhile real-world study, indicating that practice in Sweden is achieving results as seen in other countries.
After several years when we knew that new drugs for GIST were in development and trials, we are now seeing the first clinical results from Blueprint, Deciphera and other companies. The word “excitement” is being used to describe the “buzz” about these “next-generation” drugs for GIST. That was the dominant theme in the GIST session at CTOS.