LRG at ASCO 2013

ASCO was held again this year in Chicago. Over 32,000 medical professionals and exhibitors participated in what has become an international event.  53% of attendees now come from outside the US.

It helps to know that the information presented at ASCO is not peer reviewed as are journal articles.  So the level of information is not the same. Peer review can come later as ASCO reports are submitted for publication.

However, ASCO reports are screened by a Scientific Program Committee of medical professionals familiar with each cancer type.  GIST falls under the track “Sarcoma”.  The four MDs on the Sarcoma Program Committee have significant GIST experience. The abstracts submitted for review by the Sarcoma Program Committee are then given a place in the overall conference based on merit and likely impact.  The order from higher to lower is:

• Plenary Session
• Oral Abstract
• Discussion Poster
• General Poster
• Abstract only

Most of the new information collected by the LRG comes from Oral Abstracts, Discussion Posters and General Posters.

The LRG is represented by both staff and volunteer reporters who attend the presentations and walk through the poster sessions.  LRG Reporters meet via teleconference before the meeting to review the GIST abstracts and plan to see important posters and presentations.  At the meeting they collect paper copies of posters, take photos of posters, talk with authors, attend oral presentations (sometimes asking questions) and interview authors and principle investigators.  LRG reporters also carefully review the on-line video and audio archives of session material made available by ASCO for attendees.  Other activities include meeting with other patient groups, attending education sessions and attending off-site meetings.  The ASCO meeting usually starts on a Friday and goes thru Tuesday morning.  GIST oral abstracts are typically presented Monday afternoon.

Regorafenib Phase 2 Trial leads Discussion Posters at ASCO 2013

Improved benefit in Wild Type reported and combination trials indicated

The Phase 2 trial of Regorafenib in 33 GIST patients conducted in 2010 continues to produce data advancing our knowledge of GIST. Two posters based on Phase 2 trial data led the Poster Discussion session on Saturday morning.

Suzanne George, MD Dana Farber Cancer Center, Boston presented updated Phase 2 results showing prolonged disease control in patients with Exon 11.  Median Progression Free Survival (PFS) was 13 months and Median Overall Survival (OS) was 25 months.  For Exon 11 primary patients these are improvements over similar results from the Phase 2 Sunitinib trial shown in Table 1.

Drug	Patients	Median Follow-Up	Median PFS	95% CI	Median OS	95% CI
Regorafenib	19	20	13.0	10.0-21.0	25.0	16.0-NR
Sunitinib1	44	Not rep.	5.1	4.5-7.8	12.3	8.8-19.6

Table 1: KIT Exon 11 Primary Mutation Survival (Months) in Phase 2 Trials. CI – Confidence Interval, NR – Not Recorded

Regorafenib is noted for potent inhibition of KIT Exon 17 & 18 secondary mutations in GIST cell lines.  Data presented by Dr. George now shows this benefit in the clinic.  Again the data from the Sunitinib Phase 2 trial is used for comparison and is shown in Table 2. PFS was significantly improved for patients known to have Exon 17 secondary mutations.  In the lab Sunitinib is not as effective against Exon 17 mutations and this is reflected in the Phase 2 trial data published in 2008.

Whether this data is sufficient to raise the question of which drug should be given first based on secondary mutation remains to be seen (i.e. a clinical trial). Practicality may also be an issue.

Drug	Patients	Median Follow-Up	Median PFS	95% CI
Regorafenib	7	20	18.0	6.0-NR
Sunitinib1	13#	Not rep.	2.3	1.0-5.1

Table 2: KIT Exon 17 Secondary Mutation Progression Free Survival (Months) in Phase 2 Trials. CI – Confidence Interval, NR – Not Recorded

#includes one patient with exon KIT 18 secondary mutation.

¹Heinrich, M. C. et al. Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor. J Clin Oncol 26, 5352–5359 (2008).

Perhaps the most notable data was that for what we have historically called Wild Type GIST.  Wild Type GIST is now sub-divided into those whose tumors express normal levels of SDHB and those whose tumors are SDHB-Deficient indicating a disruption or mutation in the SDH complex.  This important distinction was first identified in 2007 by a team led by Constantine Stratakis.  It occurs in approximately 40% of Wild Type patients.  Dr. George reports that of the six patients in the study with this deficiency …all had clinical benefit and two had partial responses (30%+ tumor shrinkage).  Wild Type has historically been noted for slow growth but also mixed response to therapy with stability typically the best response.  These results raise the question of the mechanism of action of Regorafenib in SDHB-deficient GIST.  The Phase 3 trial of Regorafenib included 29 Wild Type patients reported by George Demetri in his presentation on plasma DNA.   Hopefully SDHB deficient data will be available to see if improved outcome was also seen there in this subset of Wild Type patients.

Reports of the Phase 2 trial of Regorafenib continue to show longer Progression Free Survival compared to reports from the phase 3 trial.  The Phase 3 PFS results (median 4.8 months) are less than half the Phase 2 (median 13.0 months).  This is a significant difference since the 95% confidence limits do not overlap.   A possible explanation could be the mix of mutation types.  In the Phase 3 only about half the patients had primary mutation analysis.  Given the potential for differential response by primary (and now secondary) mutation it is becoming increasingly relevant in clinical trial settings to have complete sub-group analysis of these biomarkers to validate responses, avoid false negative results due to confounded data and to find patients who benefit the most.

In the second poster Cèsar Serrano-Garcia, MD also of Dana-Farber presented data showing the relative effectiveness of Sunitinib and Regorafenib against the most common secondary KIT mutations.  Sunitinib is particularly good for Exon 13/14 ATP binding pocket (Gateway) mutations and Regorafenib is effective against Exon 17/18 kinase activation loop (A-loop) mutations.  The thrust of the poster is that some combination of the two drugs would produce the best result.  As a result of his work Serrano-Garcia will receive a $50,000 Young Investigator Award from Conquer Cancer Foundation of ASCO for “Cycling Multi-Kinase Inhibitors in Imatinib-resistant GIST to Maximize Clinical Response”.  It is anticipated that this work will eventually result in a combination clinical trial in GIST[J1] .

A third poster presented by Heikki Joensuu, MD Helsinki University, Finland reported the details of the sub-group analysis of patient characteristics for the Regorafenib Phase 3 trial.  All patient sub-groups showed significant benefit on Regorafenib compared to their counterparts on placebo.  These included groups divided by age, sex, treatment history, mitotic index and KIT mutational status.  Only patients on Imatinib for less than six months showed a benefit that was not significant. Regorafenib typically reduced risk of progression by 70% or more compared to placebo in these sub-groups.

Re-challenge with Gleevec better than no therapy

Yoon K. Kang, MD, PhD of Asan Medical Center, Seoul, Korea presented results of a randomized study comparing re-challenge with Gleevec to placebo in 70 advanced resistant patients who had failed both Gleevec and Sutent but who had also had prior clinical benefit from Gleevec.  Many had failed more than Sutent but none had had Stivarga.  The results showed that the Gleevec arm had significantly longer progression free survival.  Patients on placebo were allowed to cross-over to Gleevec on progression and saw the improved level of disease control.  Although it was a small benefit (Median PFS 1.8 months) it was twice that of the patients on placebo.  When asked if he would use Gleevec instead of Stivarga for patients failing Sutent, Dr. Kang replied that he would recommend Stivarga because of the longer progression free survival reported in trials.  He stated he would reserve Gleevec re-challenge for use when all else had failed.

In his remarks discussing this report  Shreyaskumar Patel, MD from MD Anderson took up the implications for clinical trial design in GIST:  “So if the patient has run out of all sorts of options ….randomizing them to imatinib instead of placebo certainly slows down the rate of progression even in the absence of a response and certainly can impact on their quality of life and their overall natural history….This now validates what is fairly standard global practice of keeping these patients on a kinase inhibitor when all else has failed …but, more importantly, I would hope that this resets the tone and when the next  anti-GIST agent comes on to the market  for clinical trial we will use a kinase inhibitor of choice as a control arm and get rid of the placebo arm.”

Nilotinib Phase 3 versus Imatinib fails in first line GIST

In April, 2011 Novartis announced that the Phase 3 trial of Tasigna in newly diagnosed GIST patients had been halted after an independent data monitoring committee said that continuing the trial was unlikely to show that patients given Tasigna would live longer than those taking Gleevec.  Jean-Yves Blay, MD from Centre Léon Bérard, Lyon France presented the data from the trial.  Patients in the Gleevec arm had better progression free and overall survival than those on Tasigna.  Much of the difference was attributed to exon 9 patients who did significantly worse on Tasigna than on Gleevec.  The analysis for Exon 11 patients showed Gleevec was slightly better than Tasigna in PFS and OS.  Dr. Blay indicated that there would be further analysis of the OS data to understand the impact of cross-over since the question was raised as to why there was an OS difference.  Wild Type patient data was not presented.  Dr. Blay however, did say that the numbers were too small to analyze but the few wild type in the trial did not show superiority on Tasigna.

Imatinib Failure Free Survival – Relapse vs. Resistance

The EORTC sponsored Phase 3 trial “Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor accrued 900 patients in 3.5 years from 2005 to 2008 primarily in Europe.  Median follow up is currently 4.5 years. Paolo Casali, MD from Istituto Nazionale dei Tumori, Milan, Italy presented the results at ASCO.

We have long known that patients who complete adjuvant Gleevec therapy have a risk of recurrence.  Upon recurrence patients are typically given Gleevec and can often regain control.  This recurrence would be considered a relapse of Gleevec sensitive tumor.  At some point however patients might experience new or existing tumor growth while on Gleevec.  This type of recurrence would be considered resistance and would typically warrant a switch to another TKI – Sutent.

In this trial the initial intent was to measure Overall Survival.  The trial was amended however due to the fortunately low frequency of deaths in the control group…the group not receiving Gleevec and getting ‘observation only’.  It was decided to use a new end point more fitting to the improved prognosis.  Imatinib Failure Free Survival (IFS) (defined as either death or the point when a patient switched from Gleevec to another tyrosine kinase inhibitor) was chosen.

Dr. Casali reported that overall there was no difference in IFS between the adjuvant group receiving Gleevec and the observation only group.  He then showed results for the Intermediate and High Risk patient sub-groups.  Intermediate risk patients showed no difference.  In the high-risk group there was increased benefit for the Gleevec group but it was not statistically significant.

In his conclusions Dr. Casali made the following points:

• IFS use supports the notion that, by substantially delaying relapse in high-risk GIST, adjuvant therapy may provide some benefit in duration of survival.
• Adjuvant imatinib does not appear to hasten the emergence of resistant clones.
• IFS is a tentative surrogate end-point for Overall Survival and deserves validation.

At the end of the last session on GIST Dr. Shreyaskumar Patel from MD Anderson summed up the current status of GIST Management:

Adjuvant:

• Post Primary Removal: Three years Gleevec is better than one for high risk GIST.

Advanced:

• First Line: Gleevec prevails.  Masitinib in Phase 3 trial.
• Second Line: Sutent is approved.  Masitinib is in Phase 3 trial.
• Third Line: Stivarga is approved.  All patient subsets benefit.
• Fourth line and greater: Re-challenge with Gleevec is better than no treatment (for those who had prior clinical benefit from Gleevec).

Future:

• Circulating DNA biomarkers may improve understanding and management of GIST

Exon 11 primary mutations predict Progression Free Survival

Jean- François Emile, MD, PhD  from  Hôpital Ambroise Paré, Boulogne, France presented the poster “Relationship of the topography of exon 11 alterations and predictive value for PFS in patients with advanced GIST: Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.”

This trial has produced many reports at ASCO over the years.

In this prospective study 167 Advanced GIST Patients with exon 11 mutations were grouped by mutation codon location.

Interestingly this cohort of exon 11 patients who were recruited after the initial B2222 Phase 2 imatinib trial in 2000 -2001 showed longer median PFS than that reported earlier 30 months and longer versus 20 months.

Dr. Emile reported that patients in group 2 had better response to imatinib but significantly lower progression free survival (Table 1)

 

Group	Codons	# of Patients	Median PFS (Mos.)
1	556 and below	41	49.4
2	557-558	74	30.6
3	559 and above	52	63.3

Table 1

Dr. Emile’s conclusion outlines the next steps and the potential impact in the clinic.   “These results deserve confirmation in other prospective series in advanced GIST and could be translated in the adjuvant setting.”

Sutent effective in patients over 65 years Monitoring important

Florence Duffaud, MD, PhD, La Timone University Hospital, Marseille, France presented the poster titled “Clinical experience with sunitinib (SU) in patients over age 65 with metastatic gastrointestinal stromal tumors (GIST): A retrospective study from the French Sarcoma Group (FSG).”

In this retrospective study the charts of 71 elderly patients (≥65 years) treated with Sutent on routine clinical practice were reviewed in 11 French Centers of the French Sarcoma Group to evaluate safety and efficacy. Median age was 74.  Roughly half received Sutent at 37.5 mg daily and half received 50 mg daily for 4 weeks then 2 weeks off in six week cycles.

69 of 71 patients experienced some level of adverse event during the first three months of therapy. Of all events 76% were grade 1-2 and were medically manageable.  The more serious grade 3-4 events represented 23% of all events.

Most frequent Grade 1-2 events were;

Grade 1-2 Event	Frequency of all Grade 1-2
Fatigue	20%
Diarrhea	12%
Mucositis	9%
Abdominal pain	8%
Hand foot syndrome	6.4%
Hypertension	4.7%

 

Dose changes and interruptions were common.  Some experienced more than one type of change.

 

Change	Number (n=71)	Percent of patients
Transient interruption of SU	38	53.5%
Permanent dose reduction	33	46.5%
Definitive interruption for intolerance	19	26%

Survival data indicates that Sutent in elderly patients compares favorably with the survival benefit reported at CTOS 2008 for patients in the international Sutent Treatment Use Phase 3 Trial. (LRG comparison …not part of poster)

 

Trial	N	Median Age	Median PFS (Mos.)	Median OS (Mos.)	All Grade Events	Grade 1-2 Events (%)	Grade 3-4 Events (%)
FSG ASCO 2013	71	74	10.2	21.0	388	295 (76%)	90 (23%)
Treat Use Phase  3	1117	59	9.4	17.3	2,775	2,343 (84%)	409 (15%)

 

Dr. Duffaud concluded that Sutent treatment is effective in elderly GIST patients yet dose reductions and interruptions for intolerance were frequent. She also recommended careful follow-up regarding tolerances in elderly GIST patients.

Frequency of Follow-up favorably impacts outcome

Erica Palesandro, MD Institute for Cancer Research and Treatment – Candiolo, Turin, Italy presented a poster titled “A risk-based individualized follow-up after complete surgery as an effective procedure to reduce the relapse impact in GIST patients.”

In this study 140 patients who had all tumor removed by surgery were grouped by risk of recurrence. For two years high risk patients had CT scans every three months and all others every four months.  Scan frequency gradually decreased to annual for high risk at year six and annual at year five for all others.  Patients who had recurrence during the study were further categorized as high and low tumor burden at recurrence.  58 recurrences were observed.  26% had recurrences within six months and 50% within 16 months.  Patients with low tumor burden had significantly longer overall survival (112 months for low burden versus 87 months for high burden).  The study provides some rationale for guidelines on follow-up which currently lack data on optimal methodology.  Dr. Palesandro concludes that this study shows in principle that follow-up can detect low burden tumor recurrence and that this might affect outcome and therefore justify the added cost.

Surgery after imatinib response improves outcome:

Baek-Yeol Ryoo, MD, PhD  from University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea presented the General Poster titled: “The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.” This data had been presented earlier at ASCO-GI in February, 2013

This poster notes that there is no study (clinical trial) to prove the benefit of surgical resection after imatinib response in comparison to imatinib treatment alone and that prospective phase 3 trials (of this question) have been terminated due to poor enrollment.

Noting the difficulty of doing this kind of study as a clinical trial the authors attempt to improve on prior retrospective analysis by using a statistical analysis technique called propensity scoring.  Propensity scoring matches patients that do and do not receive surgery based on the characteristics that indicate a likeliness to respond.  It is a way of countering likely bias in a non-randomized population.  Bias becomes more likely in a single site study due to the limited patient population and the unique aspects of the medical center.

This is a retrospective study that included 134 patients treated from 2001 to 2010 at Asan Medical Center.  Patients must have had initially metastatic GIST or a recurrence of GIST after only surgery.  Patients also must have had some benefit (Partial Response or Stable Disease) while on imatinib and the benefit must have lasted for at least six months. This sub-set of patients was then divided into those who benefited from imatinib and then had surgery (42) and those who benefited from imatinib but did not have surgery (92).

Patient characteristics included some significant differences between the two groups.  The surgery arm was younger (51 vs. 58) and the imatinib only arm had more tumors located in the peritoneum (45% vs. 23% of tumor sites). One could expect these characteristics in the clinic because younger patients are more able and likely to undergo surgery and multiple mets in the peritoneum make surgery difficult.

Despite these limitations the authors report that surgery provides significant benefit before and after adjusting for statistical bias.  Patients who had surgery had significantly improved Progression Free and Overall Survival.

“In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics”, Dr. Park said at an ASCO GI press conference in February.

Although this study sheds light on the value of surgery after Gleevec existing US guidelines have already adopted the recommendation that surgery may be indicated in these advanced patients.

In the US the NCCN Guidelines for Surgery in GIST contain the following recommendation:

Unresected or Metastatic GIST

Imatinib is the primary therapy for metastatic GIST. Surgery may be indicated for:

• Limited disease progression refractory to imatinib.
• Locally advanced or previously unresectable tumors after a favorable response to preoperative imatinib.

According to the US guidelines, the level of evidence supporting this recommendation is recognized as not at the highest level but there is uniform NCCN consensus that the intervention is appropriate.

The authors conclude: “These results strongly suggest that surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.  This treatment strategy can be recommended in clinical practice, if there are experienced multidisciplinary team, skillful surgeons and/or interventional radiologists.”

The emphasis on experience, surgical skill and a multi-disciplinary team is important to note.  Advanced GIST patients who might qualify for surgery after imatinib are well advised to seek out a known GIST center.

When commenting about this study, Neal J. Meropol, MD, professor and chief of the division of hematology and oncology at Case Western Reserve University School of Medicine, noted that although GISTs are an uncommon type of gastrointestinal tumor, they have been a triumph of molecularly targeted therapy with imatinib, with imatinib providing disease controls for years in many patients.

“Unfortunately resistance ultimately develops to imatinib, so this study provides provocative evidence that taking an aggressive approach with surgical treatment, in addition to medical treatment with imatinib, may result in an even longer survival in patients with GIST,” Meropol said.

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Mitchell Posner, MD, Thomas D. Jones Professor and chief of general surgery and surgical oncology, University of Chicago, said the study is “interesting but not groundbreaking” because it is not a randomized trial. The study will not change clinical practice as “almost everyone” is already resecting patients with residual disease or those with tumors that stop responding to imatinib, he said.

Based on previous retrospective trials, most experts agree that patients with GIST benefit from surgical removal of residual tumors. However, the previous studies did not provide sufficient evidence that surgery is beneficial because they assessed clinical outcomes in patients who had received surgery without comparison to patients who did not undergo surgery (J Clin Oncol 2006;24:2325-2331; J Surg Oncol 2008;98:27-33; Ann Oncol 2010;21:403-408).