Precision medicine for lung cancer a ‘rapidly evolving field’
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Molecular oncology is a rapidly evolving field with exciting results.
Understanding molecular oncology for targeted cancer treatment is becoming more crucial as promising studies with improved outcomes emerge and lead to new treatment approvals by the FDA.
In lung cancer, for example, FDA-approved drugs previously addressed EGFR, ALK, ROS1, BRAF and NTRK gene alterations. This was followed by treatment approvals in May addressing MET exon 14 and RET mutations.
Importantly, certain genetic mutations and tumor mutational burden (TMB) have been emerging as biomarkers predictive of response to immunotherapy, independent of PD-L1, and are under investigation and eventually may be incorporated into clinical practice.
However, an international study published in Journal of Thoracic Oncology with data from 102 countries showed the adoption of molecular testing for lung cancer was relatively low globally. Researchers found that fewer than 50% of patients with lung cancer received molecular testing, with the low rate due to barriers including cost, access, quality, turnaround time and lack of awareness.
These barriers need to be addressed to get more benefit from molecular oncology in clinical practice worldwide. Below is a summary of clinically promising targets for lung cancer that should be routinely tested for in our patients to improve the clinical outcome.
MET inhibitors
MET inhibition is one of the latest forms of targeted treatment for lung cancer, and anti-MET therapies include selective tyrosine kinase inhibitors, nonselective TKIs (multitarget) and antibodies against MET or its ligand hepatocyte growth factor.
In a phase 2 study published in May in The New England Journal of Medicine, Paik and colleagues observed a 46% overall response rate among 99 patients with advanced non-small cell lung cancer with confirmed MET exon 14 skip mutation who received the highly selective MET inhibitor tepotinib (Merck KGaA). The median duration of response was 11.1 months.
Five patients with additional MET gene amplifications appeared to have significant responses, as well.
Wolf and colleagues presented results of another trial, the phase 2 GEOMETRY mono-1 study, during the ASCO20 Virtual Scientific Program. In the study, 84 pretreated or treatment-naive patients with advanced NSCLC who had MET gene amplification (gene copy number 10), but not MET exon 14 skip mutation, received capmatinib (Tabrecta, Novartis), another highly selective MET inhibitor. Researchers reported ORRs of 29% for pretreated patients and 40% for treatment-naive patients.
For pretreated patients, median PFS was 4.1 months and median OS was 10.6 months. For treatment-naive patients, median PFS was 4.2 months and median OS was 9.6 months.
In May, the FDA approved capmatinib as a treatment for patients with metastatic NSCLC who have the MET exon 14 mutation, with anticipation of expanding the current therapy designation.
Among several other anti-MET agents, preclinical data suggested telisotuzumab vedotin (ABBV-399, AbbVie) was well-tolerated in a phase 1 study, with objective responses in c-Met-expressing NSCLCs (EGFR-mutated, 34.5%; nonmutated, 28.6%). An ongoing phase 2 study (NCT03539536) is evaluating this agent as second-line therapy for NSCLC.
In light of the positive results in patients with NSCLC who harbor the MET exon 14 mutation or MET amplification, future studies combining anti-MET drugs with other agents might be promising.
Targeted therapy against RET fusions
The FDA approved selpercatinib (Retevmo, Eli Lilly), a selective RET kinase inhibitor, in May for patients with NSCLC or thyroid cancer who harbor the RET mutation.
The accelerated approval was based on remarkable results of the phase 1/phase 2 LIBRETTO-001 trial presented in 2018 at ASCO Annual Meeting and in 2019 at the World Conference on Lung Cancer (WCLC) and European Society for Medical Oncology Congress.
Data presented at WCLC showed that among 105 previously treated patients with RET fusion-positive NSCLC, treatment with selpercatinib resulted an ORR of 68% with a median duration of response of 20.3 months.
The drug also demonstrated central nervous system activity, with an ORR of 91% for the 11 participants with brain metastases at baseline.
Another promising RET inhibitor, pralsetinib (BLU-667, Blueprint Medicines), was recently approved by the FDA to treat advanced RET fusion-positive NSCLC based on phase 1/phase 2 ARROW trial preliminary data, presented during the ASCO20 Virtual Scientific Program. ORR for nine patients with CNS metastases who received pralsetinib was 56%; three patients had a complete response.
Turning Point Therapeutics’ dual RET/SRC inhibitor, TPX-0046, also is being tested in a phase 1/phase 2 study in patients with advanced solid tumors including NSCLC harboring RET fusions or mutations (NCT04161391).
EGFR-mutated NSCLC
During this year’s ASCO virtual meeting, Herbst and colleagues presented results of the phase 3 ADAURA trial, in which patients with stage IB to stage IIIA NSCLC with EGFR mutations (exon 19 deletion, L858R) received adjuvant therapy with the EGFR TKI osimertinib (Tagrisso, AstraZeneca) or placebo for 3 years.
Researchers reported higher 2-year DFS rates with osimertinib vs. placebo for patients with stage IB (87% vs. 73%), stage II (91% vs. 56%) and stage IIIA (88% vs. 32%) disease. The trial was unblinded early because of these early superior DFS results with osimertinib.
Although an OS snapshot of patients with stage II/stage IIIA disease showed a HR of 0.4 favoring osimertinib, OS in the study remains immature.
Another phase 3 study presented at ASCO this year, CTONG1104, showed adjuvant gefitinib (Iressa, AstraZeneca) prolonged DFS (28.7 months vs. 18 months), but not OS, vs. chemotherapy for patients with resected EGFR-mutant lung cancer.
EGFR mutations are well-known and occur in about 10% to 15% of all advanced NSCLC. EGFR exon 20 insertions seem more refractory to known agents against EGFR mutations compared with more common EGFR mutations, such as L858R and exon 19 deletions.
Data presented at ASCO regarding two agents, poziotinib (Spectrum Pharmaceuticals) and TAK-788 (Takeda Oncology), both EGFR exon 20-directed inhibitors, showed promising responses in refractory NSCLC with EGFR exon 20 insertions. FDA approval may be sought for these two agents.
Epigenetic therapy
Despite curative-intent surgeries removing primary tumors for variety of early-stage cancers, metastatic disease can still develop and lead to death. A report in Nature by Lu and colleagues showed that, in mouse models of pulmonary metastases, adjuvant epigenetic therapy using low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat (Syndax) following surgical removal of primary lung, breast and esophageal cancers could alter the ability of circulating myeloid-derived suppressor cells to transform an area into a metastatic niche by disrupting the premetastatic niche. This intervention resulted in longer periods of DFS and increased OS. The preclinical study suggests adjuvant epigenetic modifiers may disrupt the premetastatic microenvironment and inhibit metastases. This preclinical evidence supports the potential role of epigenetic therapy, which may translate into clinical studies in the future.
Genomic biomarkers for immunotherapy
TMB and PD-L1 have been shown to be independent predictive variables of immune checkpoint inhibitor (ICI) response.
Recent studies suggest several oncogenes and tumor suppressor genes are potential predictors of ICI response. These include, but are not limited to, STK11, KEAP1, PTEN, beta-catenin and beta-2 microglobulin.
Although genomic tumor characteristics do not influence our current treatment decisions in immunotherapy, they eventually can be utilized in clinical practice for precision medicine in cancer immunotherapy.
References:
Camidge DR, et al. Abstract 3011. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Drilon A, et al. Abstract PL02.08. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Lu Z, et al. Nature. 2020;doi:10.1038/s41586-020-2054-x.
Paik PK, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2004407.
Smeltzer MP, et al. J Thorac Oncol. 2020;doi:10.1016/j.jtho.2020.05.002.
The following were presented at ASCO20 Virtual Scientific Program; May 29-31, 2020:
Gainor JF, et al. Abstract 9515.
Herbst RS, et al. Abstract LBA5.
Horn L, et al. Abstract 9580.
Le X, et al. Abstract 9514.
Wolf J, et al. Abstract 9509.
Wu YL, et a.. Abstract 9005.
For more information:
To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik@brown.edu.
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