CTOS 2020 Virtual Session – Key Highlights

CTOS 2020 was conducted virtually from November 18th through the 21st, and was, as usual, a well-attended event. Understandably, given the nature of our current environment, much of the content of the conference centered on COVID-19 and its impact on cancer patients, but there were a number of sessions and presentations and posters devoted to GIST as well. The Life Raft group was well-represented, with our Vice President of Programs, Sara Rothschild participating in an expert panel and the presentation of a poster. In this article I will attempt to highlight some of the main presentations and posters.

In this first group we will focus on the studies that were presented at the Friday morning GIST session. This session was chaired by Cesar Serrano, MD, PhD, head of the Sarcoma Translational Research Program in the Department of Medical Oncology at Vall d’Hebron Institute of Oncology (VHIO) in Barcelona, Catalonia, Spain. He was joined by a discussant, Ronald DeMatteo, MD, the Chair of the Department of Surgery at the Hospital of the University of Pennsylvania, who introduced and briefly summarized all of the papers, and two panelists: Chandrajit P. Raut, MD, the Chief of the Division of Surgical Oncology, BWH Center for Sarcoma and Bone Oncology Professor of Surgery, and Distinguished Chair in Surgical Oncology Surgery Director in the Department of Surgery at Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School and Piotr Rutkowski, MD, PhD, the Head of Department of Soft Tissue/Bone Sarcoma and Melanoma, and Professor of Surgical Oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland. The studies will be listed in the order they were presented, and I will attempt to describe each study and summarize its conclusions as well as potential impact on GIST patients.

Paper 22 – HUMAN SUCCINATE DEHYDROGENASE-DEFICIENT GASTROINTESTINAL STROMAL TUMORS ARE SENSITIVE TO TEMOZOLOMIDE VIA INDUCTION OF ER STRESS AND DNA DAMAGE

Paper Presenter(s): Jason Sicklick, MD; Professor of Surgery, Department of Surgery, University of California, San Diego

One of the key challenges in developing drugs for GIST is creating cell lines that can be used to test these drugs. While this is difficult in general, creating and maintaining cell lines for the SDHx deficient variant of the disease has been particularly so. Dr Sicklick was able to produce cell lines for SDHx deficient GIST and use it to determine sensitivity to temozolomide, a drug for which he is currently doing a phase II clinical trial. This is important for two reasons; first, it establishes that SDHx deficient GISTs do have some sensitivity to temozolomide and also helps us understand the mechanism, which is important not only in terms of the current clinical trial but also to help inform development of any future treatments using it. Perhaps equally as important however is the demonstration that SDHx deficient cell line creation and cultivation can be done. This may prove to be a valuable tool when developing new treatments for SDHx patients with further compounds yet to be discovered. The hope is that this accelerates the development of any new treatments for this population, for which very few options are currently available.

Paper 23 – ASSESSMENT OF A GUIDELINE-BASED FOLLOW-UP STRATEGY AFTER COMPLETE SURGERY IN PATIENTS AFFECTED BY GASTROINTESTINAL STROMAL TUMOR (GIST) WITH LOW-RISK OF RECURRENCE

Paper Presenter(s): Lorenzo D’Ambrosio, MD PhD; Medical Oncologist, Candiolo Cancer Institute & Cardinal Massaia Hospital;Torino, Piemonte, Italy

Per the authors, there is currently no standard protocol for follow-up for low risk GIST patients post-surgery. To better understand what might inform such a protocol, they performed a retrospective study of 554 low-risk patients treated within a number of sarcoma centers in Italy, and identified if progression was found. If it was, they counted the number of tests (usually imaging, such as CT scans, but also any non-imaging tests that could identify progression) that occurred up to the progression. A number of outcomes were measured – Disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), and second-tumor specific survival (ST-SS), all of which were estimated according to the Kaplan and Meier method. Statistical analyses were also performed to see if there were any other variables associated with recurrence as well as with survival. The patients were fairly evenly divided among male (52.7%) and female (47.3%), as well as age at diagnosis (57.9% under 65, 42.1% 65 or over, with an age range of 18 to 86 years). The majority of the tumors were found in the stomach (68.4%), were equal to or smaller than 5 cm (78%), and had a mitotic rate of less than 5 per 50 HPF (93.1%), which makes sense given that these patients were all either low or very low risk.

When looking at the number of recurrences, the authors found 37, which is 6.8% of the patients in the analysis. Primary tumors in an area other than the stomach, as well as the presence of symptoms at diagnosis (this occurred in 36.6% of the original 554 patients in the analysis) were associated with an increased risk of recurrence. Notably, of the 37 progressions identified, 8 occurred after a period of 10 or more years from diagnosis, which led the authors to conclude that long term follow-up may be necessary, even among lower risk patients, and should be a topic of discussion going forward. The authors acknowledged that this may be a complicated discussion, as the risks of additional radiation from some imaging tests, as well as the costs of additional procedures need to be weighed when making any decisions on widespread recommendations.

Paper 24 – THE POTENT AND SELECTIVE KIT INHIBITOR PLX9486 DOSED IN COMBINATION WITH SUNITINIB DEMONSTRATES PROMISING PROGRESSION FREE SURVIVAL (PFS) IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR (GIST): FINAL RESULTS OF A PHASE 1/2 STUDY

Paper Presenter(s): Jonathan Trent, MD, PhD; Professor of Medicine, Sylvester Comprehensive Cancer Center

If you have followed the state of development of GIST treatments, particularly those for patients with multiple metastases, over the last few years, you might describe it as somewhat of a “numbers game” – meaning that the particular number, or in the case of GIST, exon, that you have, determines your treatment. Certain drugs respond best when targeted at certain exons, and there are also drugs that attempt to hit a broad range of targets – the pan-TKIs. In addition, when patients have an array of tumors that are of different exons, combinations of drugs have been used to treat patients in an effort to hit the right “numbers.” This paper details an approach that uses multiple strategies – utilizing not only one pan-TKI, but in fact two in combination so as to hit as broad a spectrum of targets as possible. One of the drugs (PLX9486) inhibits KIT primary mutations and exon 17 and 18 secondary mutations. It was combined with Sutent (sunitinib) which inhibits KIT primary mutations and exon 13 and 14 secondary mutations.

18 GIST patients, all treated with a previous therapy (all were treated with imatinib, 3 of them were treated with PLX9486 either as a single agent or combined with PLX3397, a different type of inhibitor; the median number of prior treatments they had was 4 ). There were 9 male and 9 female patients, the median age was 62, and they were divided into 3 dosing groups, and in addition to PFS had their side effects recorded as well.

Findings were encouraging. Of the 15 patients who had never taken PLX9486, the median PFS observed was 12 months, and 11 months when taking into account all 18 patients. 4 patients were still on the medication when the study reported its findings. Of these 4, 1 reported a complete response, 2 a partial response, and 1 stability. Keeping in mind that these patients had an average of 4 previous treatments provides further encouragement when looking at these results.

In addition, the drug combination was relatively well -tolerated and there were no dose-limiting toxicities in any of the 3 dosing groups (the groups were: dose level 1, PLX9486 500mg + sunitinib 25mg; dose level 2, PLX9486 1000mg + sunitinib 25mg; and dose level 3, PLX9486 1000mg + sunitinib 37.5mg) . Circulating tumor DNA analyses also showed anti-tumor activity at exons 17 and 18, which are targets for PLX9486 and exons Sutent does not target, showing some efficacy in the combined approach.

In addition to showing that this approach was feasible, the study was able to arrive at a recommended dosing level: 1000mg PLX9486 and 37.5mg Sutent once per day. The results from this study are encouraging and our sincere hope is that this approach will be further explored in subsequent studies as soon as is possible, as it does appear to be a promising therapeutic option.

Paper 25 – RIPRETINIB INTRA-PATIENT DOSE ESCALATION FOLLOWING DISEASE PROGRESSION PROVIDES CLINICALLY MEANINGFUL PROGRESSION-FREE SURVIVAL IN GASTROINTESTINAL STROMAL TUMOR IN PHASE 1 STUDY

Paper Presenter(s): Suzanne George, MD; Director Clinical Research, Sarcoma Center, Dana-Farber Cancer Institute

Ripretinib was recently approved as a 4th line treatment for GIST and is currently in trial for additional lines for GIST as well as other diseases. This paper details information from one of those outstanding trials, a phase 1 study that is looking at the impact of dose escalation after patients progress while on the trial. Patients were given the standard recommended dose (150 mg per day) and were then monitored. If a patient progressed, they were then escalated to a total of 300 mg (150 mg given twice a day) and monitored again until 2nd progression. Progression Free Survival as well as any side effects were then noted in these patients.

There were 142 total patients in the trial, and 64 of them (45%) experienced progression. The breakdown by treatment line is as follows:

Looking at the table there are a few things to note. All of the PFS numbers are median values – note that the author captured multiple progressions, noted by PFS1 and PFS2. The initial group consists of all of the participants, so it includes both progressors and non-progressors. When the progressors are isolated out, we can see their median performance. While normally progressors and non-progressors should not be compared, it makes sense in this case, as this attempts to measure additional benefit after the progression (and subsequent dose escalation). Patients who progressed were able to obtain some additional benefit after dose escalation. This benefit somewhat decreased by treatment line but is still somewhat substantial. In addition, the authors observed that the side effects and safety profile were fairly similar on both the lower and higher doses.

These findings are relevant to GIST patients as they demonstrate that Ripretinib can be escalated fairly safely, and that doing so after progression may yield additional benefit, perhaps giving patients an additional option. In addition, given that Ripretinib is currently in a trial for 2nd line, it should be interesting to see how the findings of this trial may have an impact if Ripretinib is ultimately approved for 2nd line as well.

Paper 26 – CHARACTERIZATION OF THE EXTENSIVE HETEROGENEITY OF KIT/PDGFRA MUTATIONS IN PATIENTS WITH FOURTH-LINE ADVANCED GASTROINTESTINAL STROMAL TUMOR: GENOMIC ANALYSIS OF THE PHASE 3 INVICTUS STUDY

Paper Presenter(s): Sebastian Bauer, MD; Director Sarcoma Program and Translational Sarcoma Research, Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Nordrhein-Westfalen, Germany

Also related to Ripretinib, the drug analyzed in the study by Dr. George in Paper 25 (Dr. George was also involved in this study as well), this study took a look at the INVICTUS trial that resulted in Ripretinib’s approval as a 4th line treatment for GIST, and characterized the mutations of the trial participants. In addition to mutational samples (which were obtained by performing next generation sequencing on tumor tissue), circulating tumor DNA testing was also performed. 129 patients were in the analysis, with 128 providing tumor samples for mutational analysis and 122 plasma samples for ctDNA testing.

Mutational analysis revealed the following breakdown:

These findings are somewhat consistent with what is observed in the general population, which shows the fairly representative nature of the Ripretinib study. However, when you dig a little deeper, more of the story is revealed. Among the Exon 11 and 9 patients, who make up the majority of the analysis, 67% had at least 1 secondary resistance mutation, and 9% had 2 or more. Quoting directly from the study will serve to highlight the efficacy of also testing with ctDNA:

“ Notably, primary KIT/PDGFRA mutations were found in plasma in 78% of patients. Plasma sequencing revealed secondary resistance mutations in at least 1 exon in 70% of KIT/PDGFRA primary mutant GIST and 24% of patients had 2 or more exons affected. Patients with KIT exon 9 primary mutations exhibited fewer resistance mutations than those with exon 11 primary mutations. In 3 PDGFRA mutant cases, only a single PDGFRA mutation in exon 18 was detected. In aggregate, combined tumor and plasma biopsies allowed detection of resistance mutations in 73% of patients. Resistance mutations were detected in up to 4 exons (KIT exon 13/14/17/18 mutation) within a single patient”

This is important in that it underscores the need for as broad an approach to testing as possible so that detection rates improve. It also shows that in previously treated patients such as these, tumor heterogeneity may be more extensive than it appears, which highlights the need for broad spectrum approaches. Lastly, this innovative use of ctDNA further illustrates the need to continue to improve on that technology so it can become more widely adopted.

GIST POSTERS:

While there were plenty of presentations, there were also plenty of posters as well. One of them in particular we would be remiss in not mentioning:

(Poster 058) (GIST) PATIENTS WITH KNOWN MUTATION TRANSITION TO SUBSEQENT TREATMENTS AT A HIGHER RATE AND HAVE SUPERIOR SURVIVAL COMPARED TO PATIENTS WITHOUT KNOWN MUTATION: RESULTS FROM THE LIFERAFT GROUP (LRG) GIST REGISTRY

The lead author and presenter of this poster was the LRG’s own Jerry Call. Additional authors included other members of the LRG as well as Dr. Jonathan Trent. The poster was based on a retrospective analysis of data from the LRG registry and analyzed patients with a known mutation vs those with an unknown mutation and compared survival as well as the number of treatments the patients experienced. This comparison, which used data from 2004 (a cutoff chosen as mutational testing became more widely available at about that time) until January 2020, was also done by different treatment lines. Here is an excerpt from a chart that shows the overall survival of patients by mutation status and treatment line:

The study found that patients with a known mutation have superior overall survival when compared to those with an unknown mutation, and this difference is statistically significant, for all 3 treatment lines. There are many reasons this may occur, such as being a proactive patient and having access to GIST experts. It must also be mentioned that those with a known mutation were more likely to transition to subsequent therapies and thus have more treatments. Given the current nature of the most recent drugs for GIST and other cancers (which GIST patients do sometimes take in the off-label setting) being targeted to specific mutations this is somewhat not surprising, but further highlights the need for widespread mutational testing and specificity of treatment – a theme that was somewhat echoed throughout the aforementioned presentations as well. It is also worth noting that while having access to GIST experts and being a proactive patient may improve outcomes, the reverse may be true as well, meaning that there are those patients that cannot benefit from this due to barriers, some of which may not yet be readily understood, and warrant further study.

In summation, while this CTOS may not have been exactly like those in the past (2020 has undoubtedly been a year like no other in that regard), it still was, as always, able to provide some interesting studies that could prove pivotal for the future of GIST – and as always we will continue to follow these and any new findings based on these studies and inform you as we learn more.