Later Line therapies for patients with GIST
Gastrointestinal Stromal Tumors: when FDA approved treatments run out
Obligatory—this is not medical advice
Many times in oncology we’re faced with a situation where data is limited. This is particularly true when multiple lines of therapy have failed a patient. In patients with a diagnosis of advanced gastrointestinal stromal tumor (GIST), this is usually after four treatments. These patients have been failed by imatinib, sunitinib, regorafenib, ripretinib and are well enough to receive treatment. Nonetheless, they are without an FDA approved option. Clinical trials are available in this setting, and for those patients who find themselves in a position to do so, they should seek them out. 1 Altered dosing of previously utilized treatment may be an option. 2 Re-challenge with previously effective agents could provide disease control. 3 Let’s talk about what we know.
Clinical Trials
I think that before we enter the bulk of the discussion, we must mention that there are multiple clinical trials taking place for patients who have GISTs within the later lines. Two notable trials in this space are:
For interested patients near any of the listed centers, it would be reasonable to reach out to their contacts (listed on the clinical trial website). Each trial has distinct inclusion criteria. While these are sometimes options, it is important to ensure that one speaks with the study team to see if one qualifies.
Later line considerations
Multiple medications have been trialed at various points in the history of GIST drug development. There are many which could be used in this space. Herein, we’ll briefly touch on the following:
Pazopanib
Ripretinib 150mg BID
Imatinib Rechallenge
Pazopanib
Pazopanib is a tyrosine kinase inhibitor. See the beginning of the post about Sunitinib for an explanation as to the nature of TKIs. The specific targets that pazopanib hits are listed below. Clearly, there are a few.6
The PAZGIST study was a single-arm phase II trial that was a Simon’s two-stage design.7 It tested the efficacy of pazopanib at a dose of 800mg daily in patients with GIST refractory to imatinib and sunitinib.8
It was powered to detect disease control rate at 12 weeks by RECIST criteria, defined as patients with the following:
Stable disease (for target diameters, no growth >20% or decreased size >30%)
Partial response (reduced size of target diameters >30%)
Complete response (disappearance of target lesions)
In total, 72 patients enrolled (as it passed the first stage of the design). Here at the patient characteristics.
The disease control rate was 44% at 12 weeks, with 2 partial responses and 30 patients with stable disease. The median progression free period was 19.6 weeks. The Kaplan Meier curve for progression free survival is below.
Please note the figure above includes confidence intervals. The dark green line is the one for patients on study. Also, note that the x-axis is a little difficult to interpret. Adverse events were comparable to other trials with pazopanib at this dosing, which is to say that there were relatively high rates of toxicity. Two patients died prior to week 12 of treatment, and five further patients were not assessable at week 12. It is not mentioned whether these were attributable to treatment.
There remain open questions as to the applicability of pazopanib for patients with quad-refractory GIST. While it could be a suitable option for some patients, nonetheless, given the potential toxicity, there should be significant values-based discussion prior to embarking on treatment. Such questions may be answered with randomized trials within this space.
Ripretinib 150mg twice daily
The INVICTUS trial was a double-blind, randomized, placebo-controlled phase 3 trial for patients with at least triple refractory GIST. 9 Ultimately the result from this trial led to the approval of ripretinib. Full discussion of this trial will take place in a separate post. As an adjunct to the INVICTUS study, intrapatient dose escalation (meaning increased dose) of ripretinib was allowed at time of progression on ripretinib.10
What happened was:
Patient enrolled and placed on ripretinib at 150mg daily (per INVICTUS)
At progression, dose increased to ripretinib 150mg twice daily
Patients were followed for progression free survival, defined by mRECIST. mRECIST is different from RECIST criteria, as, instead of looking at the size of target lesions, instead it looks at the ‘enhancement’ on the arterial phase of a CT scan.11 See the figure below.
Basically, mRECIST is attempting to define a separate surrogate endpoint which characterizes the ‘functional’ aspect of the tumor. Just like size, it has its innate limitations. We are talking about shadows on a computer screen. The ideal metric for clinical trials is patient focused endpoints such as symptoms or survival.
Back to the data, however, patients who were placed on the increased dose had a median progression free survival of 3.7 months on the twice daily dose. Prior to being placed on this dose, their average time to progression was 4.6 months on the once daily dose.
Above is the progression free survival on the increased dose for patients. An interesting component of this trial was they did provide comparison of side effects at both doses, see table 2 from the paper:
One needs to point out that side effects from the first column were not counted in the second column, as ‘TEAEs continuing over from the ripretinib 150 QD period were not counted.’ It seems that some of these would be difficult to disentangle. This may imply that the denominator of each would be altered, albeit that this is not necessarily reflected in the numbers. Nonetheless, I think it’s pertinent when we take the percent of patients with alopecia and constipation into context.
All in all, this is meaningful information that was added on in somewhat of an exploratory fashion, likely borrowing from experience with imatinib, to see if additional progression might be prevented with ripretinib dose escalation. I think that it bears consideration to increase ripretinib dose for patients tolerating the medicine well who have progressed on the once daily formulation.
Rechallenge
Many times in oncology, the mantra is to keep moving forward. The concept of rechallenging with previously used agents has gained traction recently, although this has not been well quantified. Although limited, as it is retrospectively tabulated, data from Italy have suggested that patients may benefit from rechallenge treatment with imatinib or sunitinib. In an abstract from the ASCO 2017 meeting, later published, findings for 82 patients were described.1213
These patients had been failed by: imatinib, sunitinib, and regorafenib
74 patients were restarted on imatinib at 400mg daily and 8 patients were treated with sunitinib at a personalized dose
Scans were analyzed by RECIST or CHOI criteria. That stated, frequencies of scans, and the like were probably not standardized, although reference was made to imaging every 12 weeks. The median time to progression in patients was 5.4 months and the survival was 10.6 months.
These data are retrospective and probably only represent a select population of patients qualifying for later line therapy and routine imaging. That said, they still are intriguing. They likely indicate that future, later line trials, would benefit from active control of rechallenge, or other therapies.
Conclusions
Later line therapy for patients with GISTs failed by multiple types of therapy is a space without great data. While clinical trials should be considered for eligible patients, other reasonable options exist for patients who are motivated. Depending upon anticipated or prior tolerance to each of these medications, an appropriate discussion should be held between patients and their oncologists about the merits of each.
https://clinicaltrials.gov/ct2/show/NCT05160168
https://pubmed.ncbi.nlm.nih.gov/34313371/
https://ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.11038
https://clinicaltrials.gov/ct2/show/NCT05489237?recrs=a&cond=Gastrointestinal+Stromal+Tumors&draw=3&rank=28
https://clinicaltrials.gov/ct2/show/NCT05160168?recrs=a&cond=Gastrointestinal+Stromal+Tumors&draw=3&rank=31
https://onlinelibrary.wiley.com/doi/full/10.1111/gtc.12022
https://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx
https://pubmed.ncbi.nlm.nih.gov/34271307/
https://pubmed.ncbi.nlm.nih.gov/34313371/
https://www.sciencedirect.com/science/article/pii/S2211568414001569?ref=cra_js_challenge&fr=RR-1
https://journals.sagepub.com/doi/10.1177/1758835918794623
https://ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.11038