New advances in targeted therapy resistance mechanisms and treatment strategies for gastrointestinal mesenchymal tumors
Gastrointestinal stromal tumor (GIST) is the most common tumor of mesenchymal origin in the gastrointestinal tract, with an incidence ranging from 0.66 to 2.20 per 100,000 in epidemiological studies. Liu Puxiang, Department of Medical Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong Province, China
The abnormal activation of the platelet-derived growth factor receptor α (PDGFRA) tyrosine kinase and KIT with functional mutations are key factors in the pathogenesis of GIST. KIT mutations are mainly located in exon 11, including deletion mutations (about 66.9%), point mutations (about 21.5%) and duplication mutations (about 8.8%).
PDGFRA mutations were mainly concentrated in exon 18; insulin-like growth factor receptor (IGFR) overexpression was found in some wild-type patients; and BRAF V600E mutation was detected in about 13% of wild-type GISTs.
Imatinib is the main target drug for GIST, a small molecule tyrosine kinase inhibitor (TKI) that targets c-KIT, PDGFRA and bcr-abl as pseudosubstrates to compete with ATP for binding to the KIT/PDGFRA receptor tyrosine kinase site, thereby exerting a signaling effect that inhibits kinase activation. activation of signaling.
As a first-line drug for unresectable or metastatic GIST, imatinib significantly improves the prognosis of GIST, with an efficiency rate of 40%-50% and an extended duration of stable disease (SD) in another 20%-30% of patients, with a median progression-free survival time (PFS) of less than 2 years. PFS) of less than 2 years.
Imatinib resistance is currently the most difficult clinical problem, and can be divided into primary and secondary resistance according to the time of resistance: primary resistance refers to treatment failure, including disease progression or disease stabilization less than 6 months after treatment initiation, which accounts for 10-14% of GIST patients.
It is mainly seen in patients with wild-type or PDGFRA exon 18 D842V mutation: the specific mechanism of primary resistance is not well understood and may be mainly related to the fact that imatinib only binds to KIT tyrosine kinase in its non-activated state, as well as blood levels, cell cycle alterations and other genetic mutations.
The main treatment modality for this type of resistance is to switch to second-line drugs or to increase the dose of imatinib. Secondary resistance refers to disease progression after 6 months of stable disease following effective initial imatinib treatment, and usually occurs 18-24 months after imatinib treatment. Possible mechanisms include (1) secondary mutations in genes, such as KIT exons 13, 14 and 17, which are detected in 45%-65% of secondary resistance patients; (2) KIT receptor amplification; ( 3) signal bypass appearance or KIT deletion.
In contrast to primary mutations, which are characterized by a relatively homogeneous mutation site, secondary mutations are often polyclonal and diverse. liegl et al. found that secondary mutations were present in 83% of 14 patients with imatinib or sunitinib resistance, of which 2-5 new mutations were found in 67% of metastatic specimens and two new mutations in the same lesion in another 34% of patients.
Secondary mutations were found in patients with original KIT exon 11 mutations (73%), followed by exon 9 mutations (19%), and no mutations occurred in wild-type or KIT-negative GIST patients even after imatinib treatment. Gao et al. reported that the detection rate of secondary mutations was 65.8% in 38 patients with imatinib resistance. Mutations in exons 13, 14, 17 and 18 were found in 10, 1, 12 and 2 cases, respectively.
Activation of signaling bypass is also a mechanism of secondary resistance to imatinib. In a tumor-bearing mouse model, the use of imatinib has shown that the use of imatinib can upregulate the integrin signaling pathway in the cell membrane, which in turn activates the tyrosine-dependent channels FAK and Src family kinases and promotes tumor cell proliferation.
Hou et al. found that the stem cell factor SCF-mediated ligand-dependent pathway was an independent pathogenesis of GIST, independent of KIT white body phosphorylation, and that this pathway could not be inhibited by imatinib, and that upregulation of SCF expression was detected in patients treated with imatinib, which may be related to the development of secondary resistance to imatinib.
Tumors grow rapidly after GIST resistance and rarely have the opportunity to be surgically resected again. Therefore, the issues of target drug selection and treatment strategy after imatinib resistance are hot topics of current research.
Imatinib plus dosing or reuse
The NCCN guidelines recommend that imatinib may be dosed to 800 mg/d in the event of disease progression on imatinib therapy, except when poor adherence can be ruled out as an effect, based on the findings of increased clearance after 1 year of imatinib maintenance therapy and the clinical benefit of increased plasma concentrations. The effectiveness of imatinib plus dosing has been confirmed by the results of large clinical trials.
Two phase III clinical trials, EORTC 62005 and SWOG S0033, compared the efficacy of imatinib at 400 mg/d and 800 mg/d in patients with progressive GIST. The SD and partial response (PR) rates were 27% and 2g% and 2% and 7%, respectively, in the cross-over patients. A subgroup analysis found that patients with KIT gene exon 9 mutations benefited from imatinib plus dose therapy.
ESMO also recommends first-line treatment with imatinib 800 mg/d for c-kit exon 9 GIST.
Li et al. reported that dosing to 600 mg/d after imatinib resistance in 47 Chinese patients resulted in 40.4% disease control, a median PFS of 17 weeks (95% CI: 3.9-30.1), a median OS of 81 weeks, and tolerable adverse effects such as edema, malaise, rash, and neutropenia. Among the 30 patients tested for the mutation, those with the exon 9 mutation had a significant advantage in prolonged PFS, with a median PFS of 47 weeks.
Therefore, the upward dose adjustment of imatinib in the Chinese population should be done in steps starting from 600 mg.
Since imatinib at a dose of 400 mg/d is required to achieve the desired therapeutic effect, disease progression due to poor patient compliance should be fully excluded before considering imatinib resistance. The median PFS was 6.1 months in the discontinuation group, compared with 18 months in the maintenance group.
Despite this, some patients were still sensitive when re-introduced to imatinib. In 2011, the SSGX VIII/AIO phase III trial reported similar results, with 84% of patients who discontinued imatinib after 1 or 3 years of treatment achieving CR, PR or SD with imatinib. Therefore, reintroduction of imatinib in patients who progressed after imatinib discontinuation is a recommended option.
Second-line dosing
Sunitinib is a small molecule multi-target tyrosine kinase inhibitor that inhibits multiple receptor tyrosine kinases associated with tumor growth and angiogenesis, and was approved by the FDA in 2006 for second-line use in GISTs that are intolerant to imatinib or have disease progression after treatment.
Data from studies in Eastern populations now suggest that a strategy of 37.5 mg/d (continuous dosing) not only achieves the same efficacy as the standard dose of 50 mg/d (4 weeks of treatment with 2 weeks off), but also reduces the non-hematologic toxicity of sunitinib, which is recognized by many physicians with experience in sunitinib treatment in China. Recent studies have shown that sunitinib is also a viable and effective option for advanced GIST.
Although sunitinib has further efficacy in patients with imatinib-resistant GIST, it does not benefit all imatinib-resistant patients. Moreover, the occurrence of sunitinib resistance is gradually increasing. It is believed that patients with mutations at different exon sites exhibit different sensitivity to sunitinib and that secondary mutation sites may be one of the mechanisms by which sunitinib resistance occurs: patients with secondary mutations in exon 13 or 14 have better efficacy with sunitinib, whereas mutations in exon 17 are resistant to sunitinib.
Sequential use of imatinib
Imatinib continues to be effective in patients who have failed second- or even third-line therapy, and the NCCN notes that patients with locally progressive GISTs who have failed to benefit from an existing TKI should choose a previously effective and well-tolerated treatment modality.
Fumagalli et al. reported that 17 patients with progressive GIST who failed second- or third-line therapy and were re-treated with imatinib (5 at 800 mg/d) had 2 PRs and 5 SDs and were well tolerated. 21%.
The RIGHT study is the first clinical study to prospectively use imatinib in patients after failure of previous standard therapy (imatinib first-line therapy and sunitinib second-line therapy possibly including third-line therapy).
Of the 81 patients included in the analysis, 41 received imatinib retreatment, and the results showed that patients in the imatinib retreatment group had a median PFS of 1.8 months (95% CI: 1.7-3.6) and a risk ratio for disease progression or death of 0.45 (95% CI: 0.27-0.78, P=0.005), compared with a median PFS of 0.9 months in the placebo group ( 95% CI: 0.9-1.7): disease control rates were also significantly higher in the retreatment group than in the placebo group at 12 weeks (32% vs. 5%, P=0.0032), and 93% of patients in the placebo group crossed over to the retreatment group after progression.
This study suggests that there are still TKI-sensitive clones in secondary resistant GISTs, and that continued TKl therapy may delay GIST progression, and that this sequential treatment approach may help address tumor heterogeneity.
Other TKI formulations for third-line therapy
Regifenib is a multi-kinase inhibitor recently approved by the FDA and the European Medical Association. Its effects include anti-tumor angiogenesis, direct inhibition of tumor cell proliferation and regulation of the tumor microenvironment. As a third-line treatment option, it has shown significant efficacy in progressive GIST, with a median PFS of 4.8 months (IQR: 1.4-9.2) in the regifenib group compared to 0.9 months (0.9-1.8) in the control group (risk ratio 0.27, 95% CI: 0.19-0.39, P<0.01) compared to placebo controls receiving best supportive care; common adverse effects included grade 3 or higher hypertension (23%), hand-foot syndrome (20%), and diarrhea (5%).
Sorafenib is structurally similar to regifenib, and targets KIT, VEGFR, PDGFR, and serine/threonine kinases in the RAS/RAF/MEK/ERK pathway.
Rouhaud et al. reported 5 cases of metastatic GIST with PDGFRA exon 18 mutations treated with sorafenib, 1 of which was first-line treatment and discontinued after 6 months of follow-up due to cardiac adverse effects: 4 cases were third-line treatment after progression with imatinib, 3 of which were evaluated for SD after more than 3 months of follow-up, and 1 PR, who was maintained on sorafenib treatment until more than 21 months of follow-up.
There are few clinical case reports of drug selection based on mutation type, and this report confirms the good efficacy of sorafenib against PDGFRA exon 18 mutations.
Nilotinib, also a multitargeted kinase inhibitor, has been a leading representative of many novel oral agents in preclinical and phase I-II clinical trials, is effective against double mutations in imatinib-resistant KIT exons 11 and 13 or 17, and pharmacokinetics have shown intracellular Nilotinib concentrations 7-10 times higher than imatinib. Unfortunately, in two important phase III clinical trials, Nilotinib failed to achieve the expected results either as a third or first line regimen.
The ENESTg3 trial, an open multicenter trial of patients who failed or were intolerant to first-line imatinib and/or second-line sunitinib to investigate the feasibility of Nilotinib as a third-line regimen, showed a median PFS of 109 d and OS of 332 d in the Nilotinih arm, compared to a median PFS of 111 d and OS of 280 d in the best supportive care arm. The median PFS was 111 d and OS was 280 d in the best support group, with no statistically significant differences in either metric.
ENESTgl, a phase III randomized multicenter open trial of Nilotinih as first-line treatment, enrolled 736 progressive GISTs requiring no documented TKI use other than postoperative imatinib adjuvant therapy, and patients were randomized to the imatinib 400 mg/d group and the Nilotinib 400 mg 2 times/d group, as an interim survival analysis found The trial was terminated because an interim survival analysis found that PFS was not better in the Nilotinib group than in the imatinib group.
In the ENESTg3 trial, the investigators excluded 41 patients who had used more than two targeted agents and 10 patients for whom the second-line regimen was unknown, and the ITT analysis yielded OS for the treatment group; in fact, the median survival time (MST) of 405 d for the 197 patients who actually received third-line Nilotinih treatment was statistically different from the control group. 280 d, which is still statistically significant (p=0.02).
In addition, imaging evaluations were evaluated separately by local physicians and independent study centers, and the difference between them in determining PFS-related events was as high as 25.4%, with a corresponding abscissa of 48.4% at the study center. Therefore, it has been suggested that imaging progression alone may not indicate treatment failure and that OS may have an advantage over PFS in assessing the confidence of efficacy. In the ENESTgl trial, good disease control and a high quality of life were indeed observed in some patients.
Therefore, Nilotinib remains a potentially effective and safe alternative first-line option for patients who are intolerant to imatinib.
Dasatinib is a dual Src/Abl kinase inhibitor, and the available phase II clinical trials have shown PR and SD in 22% and 24% of 50 subjects, respectively, with SD beyond 24 weeks in 20% of cases, median PFS of 2 months, and median OS of 19 months.
Other New Non-TKI Agents
HSP90 inhibitors inhibit tumor cell proliferation and induce apoptosis by promoting the degradation of multiple substrates through the ubiquitin-proteasome pathway while blocking multiple signaling. It provides a new way to target KIT and PDGFRA mutations for GIST treatment.
IPI-504 is the first oral HSP90 inhibitor that has been shown to inhibit imatinib-resistant PDGFRA D842V mutant cell lines in vitro. It also showed better down-regulation of KIT downstream signaling and inhibition of tumor growth in a tumor-bearing mouse model, especially when combined with imatinib, with the more obvious adverse effect being hepatic adverse effects. In the phase III clinical trial, the drug treatment group was terminated due to an increase in unexpected deaths.
AT13387, another newly developed HSP90 inhibitor, has shown good inhibition of imatinib-sensitive or resistant GISTs in in vitro and in vivo trials, and enhanced antitumor effects with less adverse effects when combined with imatinib. It is currently in phase II clinical trials (Clinical Trials.gov Identifier: NCT01294202).
Pl3K/AKT/mTOR is an important pathway downstream of the receptor tyrosine kinase that is responsible for regulating cell growth, stress and functional response. The activation of mTOR in wild-type GIST is 73.9%, compared to 38.4% in KIT mutants. Therefore, mTOR pathway activation may be one of the mechanisms of drug resistance in wild-type GIST. The new drug BKM120, a PI3K inhibitor, has entered phase 1 clinical trials.
The mTOR inhibitor everolimus has completed a phase II clinical trial, in which patients were divided into two groups, one with progression after imatinib and the other with sunitinib or other TKI after imatinib progression, representing the second-line and third-line regimens, respectively. The results showed that both groups met the expected efficacy criteria: 17% and 37% of patients had 4-month PFS, respectively; median PFS was 1.9 and 3.5 months, and median OS was 14.9 and 10.7 months, respectively. In the future, the combination of everolimus and imatinib treatment regimen needs to be further investigated.
Despite the achievements of GIST-targeted therapies, close to half of imatinib-resistant patients still do not seem to benefit from various second- or third-line treatments. It is indisputable that the role of genetic analysis in predicting targeted efficacy, resistance mechanisms and guiding clinical practice in GIST is becoming more and more evident, and individualized targeted therapy for GIST guided by molecular biology is the future trend. With the development of various new drugs, more attention should be paid to prospective studies on different individualized treatment strategies for different drug resistance mechanisms in the future.