ESMO Congress 2024

I’m happy to share that our study was recently highlighted at the European Society of Medical Oncology (ESMO) Conference, a major event where experts from around the world come together to discuss the latest cancer research. Our study was selected as a poster presentation, which helps spread awareness about GIST and allows other researchers to learn more about it.

Our study, titled “Real-World Effectiveness of Imatinib in Patients with Advanced GIST: The LRG Registry,” looked at how Imatinib (IM), a treatment for GIST used for over 20 years, works in real life.

While early clinical trials showed that IM could help stop cancer from progressing for around two years,we focused on how different genetic mutations in GIST affect how well the treatment works.

We want to sincerely thank all the members of our registry. Your support and the de-identified data you provide make studies like this possible, helping us advance GIST research and creating an everlasting legacy of knowledge. If you’re not part of the registry yet and would like to contribute to future research, please contact us.

I will continue to update you with any latest developments in GIST research.

LRG POSTER PRESENTATION AT ESMO

LRG ESMO 2024 poster

Results: A total of 2,630 patients diagnosed with GIST were identified, of which 1,519 patients (57.9%) had known mutation status. We evaluated 734 advanced/metastatic GISTs by predicted IM sensitivity. While in the whole cohort mPFS was 31.2 months (95% CI 27.6-36.7), the mPFS in the IM-sensitive cohort (n=559) was significantly higher at 42 months (95% CI 36.6 – 53.9) compared to 18.8 months (95% CI 10.9 – 29.5) in the IM-intermediate cohort (n=119) and 15 months (95% CI 10.0 – 22.1) in the IM-insensitive cohort (n=120). The median overall survival (mOS) in 533 advanced/metastatic KIT exon 11 patients was 12.6 years (95% CI 11.1-14.3). The rate of extra-abdominal metastasis in 364 advanced GIST patients with KIT/PDGFRA mutations and abdominal primaries was 17% (n=61), with 47 (13%) reporting thoracic metastasis and 28 (8%) reporting bone/spine metastasis. Only one patient reported a brain metastasis (0.2%).

Conclusions: Our study shows that initial IM treatment may achieve a mPFS of over three years for IM-sensitive mutations, with a mOS >10 years. Additionally, 17% developed extra-abdominal metastases, mainly to the thorax and bones. This highlights the need to integrate mutation status and clinical-genomic data from large cohorts into GIST therapeutic development and clinical counseling.

What does this mean for patients?
Imatinib has been the main treatment for Gastrointestinal Stromal Tumors (GIST) for over 20 years. In early trials, patients lived without their cancer progressing for about two years on average. To better understand how well this treatment works in the real world, we looked at data from the LRG patient registry and focused on how different types of GIST responded to IM based on their genetic mutations. We reviewed information from the LRG Patient Registry, including details like where the tumor was in the body, the genetic mutations the tumors had, and the treatments patients received.

Results from this study showed: Out of 2,630 GIST patients, 1,519 reported a mutation. Out of these, 734 patients had advanced or metastatic GIST (meaning the cancer had spread), and they were grouped based on how sensitive their tumors were to IM.

• IM-sensitive group: These patients lived without their cancer progressing for an average of 42 months (about 3.5 years).
• IM-intermediate group: These patients had an average progression-free survival (PFS) of 18.8 months (about 1.5 years).
• IM-insensitive group: These patients saw their cancer progress after an average of 15 months (just over a year).

The study also found that 17% of patients with advanced GIST developed cancer that spread outside the abdomen, most commonly to the chest and bones, but very rarely to the brain. This study shows that for GIST patients whose tumors are sensitive to IM, treatment can help keep the cancer from progressing for over three years(this is just a median number, which means there are cases with higher numbers and lower numbers). However, some patients may still experience cancer spreading to other parts of the body, particularly the chest and bones, which emphasizes the importance of knowing the tumor’s mutation when deciding on treatment.

OTHER RELEVANT GIST PRESENTATIONS – SUMMARIES

LEVANGIST

Phase: 2
Study drug: lenvatinib vs placebo
Trial Location: France
Trial information: https://clinicaltrials.gov/show/NCT04193553

Description: The primary objective is to compare the efficacy of lenvatinib (a broad spectrum TKI) plus Best Supportive Care versus Placebo plus Best Supportive Care in the treatment of patients with advanced GIST, after failure of imatinib and sunitinib.

Patients: 77 patients were randomized to the lenvatinib arm or the placebo arm (39 received lenvatinib and 38 received placebo). 63.6% were males and 36.4% were females. 89.7% of patients have received ≥3 prior drugs.

Results: LENVAGIST showed that after 4 months of treatment, the progression-free survival (PFS) rate was 39% n=14 (95% confidence interval [CI] 23–54) in patients receiving lenvatinib compared with 11% n=4 (95% CI 3–23) in those treated with placebo (hazard ratio [HR] 0.44; 95% CI 0.27–0.71; p=0.0008). 2 partial responses were reported, both in the lenvatinib arm. 30 patients (79%) allocated to placebo switched to lenvatinib (median PFS from lenvatinib start 2.1 months (95%CI 0.9-3.7). The median OS was 14.4 months (95%CI 7.1-18.9) for lenvatinib vs 8.7 months (95% CI 5.2-14.4) for placebo (HR: 0.77, 95% CI 0.46-1.28). Median PFS was 2.8 months (95% CI 1.8-5.2) vs 1.0 month for placebo (95% CI 0.9-1.5)

Primary Endpoint ITT Population ESMO graphCitations: Le Cesne A, et al. LENVAGIST: A multicentre, comparative, placebo (P)-controlled, double-blinded, phase II study of the efficacy of lenvatinib (L) in patients with advanced GIST after failure of imatinib and sunitinib.
ESMO Congress 2024, LBA79

Proffered Paper Session – Sarcoma, 16.09.2024, h. 14:45 – 16:15, Santander Auditorium – Hall 5

What does this mean for patients?
The LEVANGIST trial is a study testing the drug Lenvatinib against a placebo (a pill with no active drug) to see if it helps treat patients with advanced GIST (gastrointestinal stromal tumors) who have already tried and didn’t respond well to imatinib and sunitinib. The study took place in France between March 2020 and January 2024.

Participants:
• 77 patients participated, with half receiving lenvatinib (39 patients) and the other half receiving the placebo (38 patients).
• Around 64% of the participants were male, and 36% were female.
• Nearly 90% of the patients had already tried 3 or more other treatments before this study.

Results from this study showed:
• After 4 months, 39% of patients on lenvatinib did not see their GIST get worse, compared to just 11% on the placebo.
• Two patients (5%) who took lenvatinib had partial shrinkage of their tumors, while none in the placebo group had that response.
• Most patients (79%) who were on the placebo switched to lenvatinib after their cancer progressed, but the median time without progression after switching was only about 2.1 months.
• The average survival time (overall survival) was 14.4 months for patients on lenvatinib compared to 8.7 months for those on placebo.

This study looked at whether lenvatinib can help slow down the growth of GIST in patients who have already tried other treatments or clinical trials. The results show that lenvatinib helped delay cancer progression for more patients compared to placebo, and some even saw their tumors shrink. However, further studies need to be done in order to have more insight in the impact of this drug in GIST.

Comparison of LEVANGIST to other GIST trials that used placebo:
Comparison LEVANGIST to other GIST trials ESMO graph

AXAGIST

Phase: 2
Study drug: Axitinib plus avelumab
Trial Location: Poland
Trial information: https://clinicaltrials.gov/show/NCT04258956

Description: To assess anti-tumor activity of avelumab in combination with axitinib in patients with unresectable/metastatic GIST after progression on second or third line treatment (after failure on at least of imatinib and sunitinib) in terms of progression-free survival (PFS)

Patients characteristics: Of the 58 patients enrolled, 56 patients were evaluable for safety and efficacy. Median age was 60 years (range 18-80), 21 patients (37.5%) were female and 35 patients (62.5%) were males. 30 patients (53.6%) had received prior 3 lines of TKIs. Median follow-up was 27.4 months.

Results: Results showed The PFS rate at 3 months was 57.1%. Median PFS was 4.6 months (95%CI, 2.9-6.4) and median Overall survival was 14.2 months (95%CI, 9.2-26.3). The 12-month PFS and OS rates were 22.8% (95% CI: 14-37.1) and 59.3% (95% CI: 47.5-74), respectively. The best response was partial response in 5 patients (8.9%), stable disease in 34 patients (60.7%) and progressive disease in 17 patients (30.4%). Among patients with partial response, the median duration of response was 18.5 months (95%CI, 18.3-NA). Adverse events occurred in 94.6% of patients; 30.4% of patients experienced grade 3 or higher adverse events, all were manageable.

What does this mean for patients?
The AXAGIST trial is a study testing two drugs, Axitinib and Avelumab, to see if they work better together in treating patients with advanced or unresectable GIST after other treatments have failed (specifically, after patients have already tried and didn’t respond well to imatinib and sunitinib). The clinical trial was conducted in Poland.

Participants:
• 58 patients participated, with 56 evaluated for how well the treatment worked and its safety.
• The average age was 60 years old, with patients ranging from 18 to 80 years old.
• About 38% of the patients were women and 62% were men.
• Over half of the patients (53.6%) had already tried 3 different treatments before this study.

Results from this study showed:
• After 3 months of treatment, 57% of patients’ cancer did not get worse.
• On average, patients went about 4.6 months before their cancer started progressing again.
• The average overall survival time (how long patients lived after starting treatment) was 14.2months.
• Partial tumor shrinkage was seen in 5 patients (8.9%), and about 61% of patients had their disease stay stable (neither shrinking nor growing).

Side Effects:
• Almost all patients (94.6%) experienced some side effects, with 30% having more serious side effects, but all were manageable.

This study is looking to see if this new combination of drugs can help stop GIST from getting worse in patients who have already tried other treatments. Most patients didn’t have their cancer grow worse right away, and some even saw a partial reduction in their tumor size.

Citation: Rutkowski P, et al. Axitinib plus avelumab in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST) after failure of standard therapy: Single-arm phase II study (AXAGIST).
ESMO Congress 2024, Abstract 1723MO.

Mini Oral Session – Sarcoma, 13.09.2024, h. 16:00 – 17:30, Alicante Auditorium – Hall 3

HQP1351

Phase: Phase 1
Study drug: olverembatinib
Trial Location: China
Trial information: https://clinicaltrials.gov/study/NCT03594422

Description: This is a multicenter, open-label Phase 1 study designed to determine the recommended dose for Phase 2 while also assessing the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary effectiveness of olverembatinib in patients with GIST or other solid tumors.

Patient Characteristics: Olverembatinib was administered orally at an assigned dose ranging 20 to 40 mg every other day (QOD). As of March 2024, 26 patients with SDH-deficient GIST (confirmed by IHC) had received ≥1 dose of olverembatinib; 50.0% of patients received ≥3 TKIs.

Results: Olverembatinib study showed that it was well tolerated at doses of 30 to 50 mg. Among patients, 6 (23.1%) achieved a partial response as their best outcome, with a median progression- free survival of 22.0 months (range: 12.9-38.6 months). In SDH-deficient cell lines, olverembatinib showed stronger antiproliferative activity compared to other approved TKIs (IC50: 0.129-5.132 μM). In PC12#5F7 cells, it reduced HIF-2α, VEGFA, and FGFR1 protein levels, while inhibiting the phosphorylation of FGFR1, IGF-1R, SRC, AKT, and ERK1/2. In xenograft models derived from PC12#5F7 cells, olverembatinib exhibited dose-dependent antitumor effects at doses of 10 and 20 mg/kg (every other day).

What does this mean for patients?
The HQP1351 study is exploring the effectiveness of a drug called Olverembatinib in treating SDH- deficient GIST, a rare subtype of GIST that has limited treatment options. Olverembatinib is already used in China for certain leukemia patients, and this trial is testing its potential for GIST. The drug is taken by mouth every other day.

Study Details
• Participants: 26 patients with confirmed SDH-deficient GIST, most of whom (50%) had already tried three or more tyrosine kinase inhibitors or TKIs.
• Treatment: Patients received doses of 30 to 50 mg of olverembatinib, which was generally well-tolerated.

Results:
• Response: 6 patients (23%) showed a partial shrinkage of their tumors.
• The median time without cancer progression (progression-free survival) was 22 months, meaning patients typically went almost 2 years before their cancer worsened.
• In lab tests, olverembatinib was shown to be more effective than other approved TKIs in reducing cancer cell growth, especially in SDH-deficient GIST cells.
• Further testing in animal models showed that olverembatinib slowed tumor growth by blocking key proteins that help cancer cells survive and grow.

Olverembatinib seems to be a promising option for patients with SDH-deficient GIST, especially those who have already tried several other treatments. It not only slows down tumor growth but also targets important proteins in cancer cells that contribute to the disease’s progression.However, this is just a phase 1 trial, more studies are needed in order to understand the potential role of olvermbatinib in SDH-deficient GIST. This however highlights the importance of treatment development and clinical trials in GIST.