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MET-Altered NSCLC: MET Exon 14 Skipping Mutations
We will now discuss new and emerging actionable mutations and alterations in NSCLC for which there are newly approved therapies or promising treatments in development. Let’s start with MET.
MET overexpression is a known driver of NSCLC aggressiveness; recently, MET exon 14 skipping mutations have been identified. They occur in 3% to 4% of nonsquamous cases (especially smokers) and 20% to 30% of those with sarcomatoid features. This is a particularly interesting mutation because, unlike EGFR, ALK, and ROS1 alterations that are largely seen in younger patients who are not smokers, MET exon 14 skipping is more common in patients with a smoking history or whose tumors have sarcomatoid features on pathology. Clinicians should aggressively look for these features under the microscope.
The majority of MET exon14 skipping mutations can be detected with DNA-based NGS, although RNA-based NGS is somewhat more sensitive.
PROFILE 1001 is an open-label, multicohort phase I study of crizotinib in NSCLC, including a METex14 expansion cohort (n = 69).[37,38] Results from this trial showed a response rate of 32%, with a median PFS of 7.3 months and a duration of response of 9.1 months.
While MET inhibition with crizotinib may be an off-label option for those with exon 14 skipping mutations, its MET IC50 of 22.5 nM is less potent than other newer MET inhibitors, including cabozantinib, savolitinib, tepotinib, and capmatinib (all with IC50 lower than 8 nM).
Capmatinib and tepotinib are 2 highly selective MET inhibitors that are currently being evaluated in advanced NSCLC. The 2 key trials of these agents to date are GEOMETRY mono-1 for capmatinib and VISION for tepotinib. Both are single-arm, phase II, multicohort studies in patients with advanced NSCLC and MET exon 14 skipping mutations. Previously treated and treatment-naive patients were enrolled, and the primary endpoint in both studies was ORR.
At ASCO 2019, Wolf and colleagues presented results from 2 cohorts from GEOMETRY mono-1: patients with 1-2 lines of previous therapy (n = 69) and treatment-naive patients (n = 28). Also at ASCO 2019, Paik and colleagues presented data from Cohort A of VISION: patients with MET exon 14 skipping mutations identified by tissue or liquid biopsy (n = 87). In both studies, the ORR was promising.
In May 2020, capmatinib was granted accelerated approval by the FDA for advanced NSCLC with MET exon 14 skipping mutations based on results from GEOMETRY mono-1.
Results from the GEOMETRY mono-1 study showed a nearly 70% response rate with capmatinib as first-line therapy, but also a very respectable 41% ORR in pretreated patients. This compares favorably with the 32% ORR with crizotinib in the PROFILE 1001 study.
In the first-line patients, the median PFS was 9.7 months, which was somewhat longer than the 5.4 months in previously treated patients. Of note, there was a good intracranial response rate of 54%, which suggests a superior CNS benefit compared with crizotinib.
Similarly, tepotinib showed promising results in first-line and second-line patients in the VISION study, with response rates of 45% to 50%. The ORR was similar in the first-line group and in subsequent lines, and the ORR was better than we saw with crizotinib, with fairly durable response. The median PFS by tumor biopsy was 11 months. Of note, even patients with CNS metastases achieved benefit with tepotinib.
On the whole, both of these MET inhibitors appear to be well tolerated with the caveat that peripheral edema is quite common, affecting more than 40% of patients (approximately 8% of cases are grade 3). Nuisance gastrointestinal symptoms are also common, including vomiting, nausea, and diarrhea.[39,40]
Another important new target in NSCLC is RET fusion proteins. RET plays a normal role in neural and genitourinary development, but RET gene rearrangements can give rise to chimeric, cytosolic proteins that are constitutively active. These RET fusions represent only 1% to 2% of patients with nonsquamous NSCLC and 10% to 20% of those with papillary thyroid carcinoma. Again, these gene fusions can be detected by DNA NGS, but RNA NGS appears to be more sensitive. There are many RET fusion partners and the most common is KIF5B.
Cabozantinib and vandetanib are both multitargeted TKIs approved for other indications.[42,43] They do target RET, but are less potent than the newer TKIs selpercatinib and pralsetinib, which are designed to hit RET with high specificity. For example, the IC50 for RET with cabozantinib is 11 nM, whereas it is 3 nM with selpercatinib and 0.4 nM with pralsetinib.[41,44,45] As a result, these newer agents have better efficacy and safety.
Selpercatinib (formerly LOXO-292) is being studied in the ongoing phase I/II LIBRETTO-001 trial. The primary endpoints are determining the maximum tolerated dose and the recommended dose for further study. In May 2020, selpercatinib was granted accelerated approval by the FDA for advanced RET fusion–positive NSCLC based on results from LIBRETTO-001.
Pralsetinib (formerly BLU-667) is being studied in the phase I/II ARROW study, which has similar endpoints.
This impressive waterfall plot from LIBRETTO-001 shows strong tumor responses (ORR 68%) with selpercatinib in the 105 patients with RET fusion–positive NSCLC and previous platinum doublet chemotherapy. The median duration of response in this group was 20.3 months, with a median PFS of 18.4 months, regardless of previous therapy. In the 34 patients without previous treatment, the ORR was 85% with the median duration of response (DoR) and PFS not reached. Overall, these results with selpercatinib show a greatly improved benefit compared with the multitargeted TKIs that have been used off label in the past.
Similarly, pralsetinib has also shown good efficacy in the phase I/II ARROW study, including a response rate of 58% in 48 evaluable patients, with a median DoR not reached at the time of presentation. Of note, benefit was observed regardless of previous treatment, RET fusion genotype, or presence of CNS metastases. Of the 7 patients who had received no previous treatment, 5 achieved a PR (71%).
Of importance, these new-generation RET inhibitors are active against intracranial metastases. These images are case examples from studies of both drugs that show nice intracranial responses to brain metastases: 91% response in 11 patients treated with selpercatinib and 78% response in 9 patients treated with pralsetinib.[47-49]
Both selpercatinib and pralsetinib are generally well tolerated. Overall, they are better tolerated than the multitargeted TKIs. In LIBRETTO-001, treatment-emergent grade 3/4 events included hypertension in 15%, increased AST in 7%, and increased ALT in 8%. In ARROW, grade 3 or worse treatment-emergent AEs included neutropenia in 13%, hypertension in 13%, and anemia in 7%.
KRAS Mutation–Positive NSCLC
KRAS is a GTP-binding protein that connects receptor tyrosine kinase activation with intracellular signaling. KRAS mutations were the first ones identified in NSCLC and are the most common mutations (25% to 33% of patients). The KRASG12C mutation occurs in 13% of patients with NSCLC. Despite substantial work to develop drugs targeting RAS for decades, to date, no therapies have been approved. This has been a very difficult target to develop drugs against. However, recent developments are promising with AMG 510 as the first KRASG12C inhibitor to enter clinical trials.
Both AMG 510 and MRTX849, another KRASG12C inhibitor, are being evaluated in early studies in patients with KRASG12C-positive tumors. In a phase I study of AMG 510 (N = 35), there were no treatment-related dose-limiting toxicities, grade 4 AEs, or serious AEs. Besides excellent tolerability, 5 of 10 patients with NSCLC achieved a PR and remained on treatment at data cutoff. The DoR ranged from 7.3 to 27.4 weeks.
In a phase I/II study of 17 patients, MRTX849 was also very well tolerated without establishing a maximum tolerated dose. A PR was achieved by 3 of 6 patients with NSCLC, and all 6 retained a PR or stable disease at Week 6. In my opinion, these 2 agents have great promise for a large piece of the NSCLC pie targeting the KRASG12C population.
TRK plays a normal role in neuronal development, differentiation, and function, and is limited to the CNS. The discovery of NTRK rearrangements and the development of inhibitors has been a fascinating story in medical oncology at large, with TRK fusions seen in a large number of tumor sites.[55-57] NTRK rearrangements occur when the tyrosine kinase domain is coupled with a 5’ fusion partner, generating a chimeric constitutively active TRK protein.
TRK fusions are relatively common in certain rare cancers, like salivary cancer, secretory breast cancer, and some pediatric cancers. In common cancers, TRK fusions are rare (eg, lower than 1% in lung cancer). That said, in patients who do have NTRK rearrangements, TRK inhibitors appear to be quite effective.[55-57] Targeting this small piece of the pie is another motivation for doing broad molecular profiling on all of our patients with advanced NSCLC.
Two pan-TRK inhibitors have been approved to date: larotrectinib and entrectinib.[58-61] To receive these agents, patients must have metastatic or difficult-to-resect malignancies plus NTRK rearrangements without acquired resistance mutations.
These TRK inhibitors are quite effective, as shown in these waterfall plots of changes in tumor size with the colors denoting the different tumor types.[62,63] This suggests that TRK inhibitors are tumor agnostic in patients with NTRK rearrangements. In 1 study, larotrectinib showed a response rate of 79% across all tumor types studied (N = 55) vs 75% in the NSCLC subset (N =12). In another study, entrectinib had an ORR of 57% (N = 54) vs 70% in the NSCLC subset (N = 10). The duration of benefit appears to be respectable with these drugs, with a median DoR of 10.4 months with entrectinib and 35.2 months with larotrectinib.
Both TRK inhibitors are able to cross the blood–brain barrier and have shown very good intracranial response rates. Recent results presented at ASCO 2019 and ESMO 2018 showed that 4 of 6 patients treated with larotrectinib had an intracranial response vs 6 of 11 with entrectinib.[64,65]
Treatment-related AEs have been seen with these 2 TRK inhibitors, but only rarely are these grade 3/4.[62,66] The most common grade 3/4 events with larotrectinib (N = 260) were increased ALT (4%), anemia (2%), and decreased neutrophils (3%). In the entrectinib study (N = 255), the most common grade 3/4 events were fatigue (2.8%), anemia (4.5%), and increased weight (5.1%). Essentially, these drugs are quite well tolerated, with very few grade 3/4 toxicities and otherwise manageable safety profiles.
In conclusion, molecular profiling is essential to determining whether targeted therapy is appropriate in the first-line treatment of patients with advanced NSCLC. That said, a large proportion of our patients will not have a targeted therapy available to them. The next section of this module will cover immunotherapies for NSCLC.
To aid in treatment planning, Clinical Care Options has developed a very useful interactive decision support tool for NSCLC treatment, which can be found at clinicaloptions.com/Lungtool. A user selects a combination of patient and disease characteristics through a series of questions, and the tool then provides treatment recommendations based on the entered characteristics from myself and 4 other experts in NSCLC care.
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