Rafal Dziadziuszko, MD, PhD
Editor’s Note: Get more highlights from ELCC 2022 from Lung Cancer Considered, IASLC’s podcast.
As rare driver mutations in lung cancer are identified and studied, it is becoming increasingly possible to treat patients in these populations with experimental or approved precision medicines. Examining these options in metastatic NSCLC was the goal of an April 1 session at the European Lung Cancer Congress 2022 titled “Oncogene Addicted Tumors,” which touched on drugs targeting MET exon 14 skipping mutations as well as RET, HER2, and BRAF alterations.
The session and a question-and-answer discussion were co-chaired by Rafal Dziadziuszko, MD, PhD, of the Medical University of Gdansk, in Poland, and Laura Mezquita, MD, PhD, of the Hospital Clinic of Barcelona, Spain, who gave one of the talks.
Also presenting were Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center; Julien Mazieres, MD, of Toulouse University Hospital, in France; and David Planchard, MD, PhD, of Gustave Roussy in Villejuif, France.
Exploring Treatments for MET Exon 14 Skipping Mutations
Occurring early in lung carcinogenesis, MET exon 14 skipping mutations can also be inherited or acquired during targeting of other driver alterations. Tumors harboring these mutations are typically found in adenocarcinoma; they tend to be aggressive, and they are associated with poorer outcomes.
Numerous MET-targeting therapies are active against these mutations, so next-generation sequencing (NGS) is recommended to guide treatment. However, overcoming diverse and often complex resistance mechanisms is a challenge, Dr. Mezquita said.
Laura Mezquita, MD, PhD
Drugs being investigated to treat these mutations fall into several buckets:
- Tyrosine kinase inhibitors. The first-generation multikinase inhibitor crizotinib demonstrated a 32% objective response rate (ORR) and a 7.3-month PFS in a phase I study. Phase II findings for selective MET TKIs — tepotinib and capmatinib (both given accelerated approval by the U.S. Food and Drug Administration), as well as savolitinib — demonstrated central nervous system (CNS) activity and ORR results above 40%, with the best results (a 67.9% ORR) in treatment-naïve patients. The most common adverse events were peripheral edema and nausea, largely mild or moderate.
- Monoclonal antibodies, including telisotuzumab vedotin, Sym015, and amivantamab, have shown promising levels of activity but are in very early development for this indication.
- Immunotherapy has demonstrated poor outcomes but may be more effective with better patient stratification, Dr. Mezquita said.
Further study should focus on helping to sequence MET-targeted drugs and developing more and better MET inhibitors to overcome resistance, she said.
Alexander Drilon, MD
Expanding the Options for RET Fusion-Positive Lung Cancers
Highly selective RET inhibitors with CNS activity are at the heart of treatment for RET fusion-positive NSCLCs and their resistance mechanisms — typically RET kinase domain alterations such as solvent-front G810 substitutions and V804, or gatekeeper, mutations.
Approved first-generation RET inhibitors selpercatinib and pralsetinib have demonstrated ORRs well above 50% and durable disease control in patients with metastatic or recurrent disease, regardless of previous treatment status. Now, Dr. Drilon said, the drugs are being tested in the stage I-III neoadjuvant and adjuvant settings.
In addition to being tested as monotherapies, selpercatinib and pralsetinib are showing promising results combined with other TKIs, such as osimertinib in patients with EGFR-mutated NSCLC that has acquired RET fusion-mediated resistance.
Newer RET inhibitors that may address resistance are being tested in patients with metastatic disease. These include the multikinase inhibitor TPX-0046 and RET inhibitors BOS172738, SYHA1815, HM06, and LOXO-260, with the RET inhibitor APS03118 also on deck for investigation in 2022.
Cancers of this type can also acquire MET, BRAF, RAS, and/or FGFR alterations when treated with selpercatinib or pralsetinib, with co-occurring resistance mechanisms an ongoing challenge, Dr. Drilon said. Trials seeking to target these types of resistance include one testing cabozantinib to simultaneously target both RET and MET alterations.
Sequencing Treatments in HER2-Mutated NSCLC
Among HER2 alterations in NSCLC, HER2 mutations in exon 20 are the rarest type. Easily diagnosed with NGS, they remain the most predictive factor for response to HER2-targeted therapy.
Julien Mazieres, MD
Dr. Mazieres reviewed options for each line of therapy:
- First line: Standard chemotherapy plus immune checkpoint inhibitors, which in one retrospective series demonstrated a 52% ORR, median PFS of 6 months, and OS of 88% at 1 year in treatment-naïve patients.However, HER2-mutation specific agents are being actively investigated. To this end, Dr. Mazieres cited the antibody-drug conjugate, trastuzumab-deruxtecan, which demonstrated an ORR of 54.9% with a PFS of 8 months in the phase II DESTINY-Lung01 trial, albeit with a 26% rate of interstitial lung disease.
- Second line: Clinical trial options include DESTINY-Lung 02, which is testing trastuzumab-deruxtecan, or investigations of novel TKIs, such as pyrotinib.Outside clinical trials, first-generation TKIs such as trastuzumab, given with docetaxel and possibly pertuzumab, are preferable to docetaxel alone, Dr. Mazieres said.
- Third line: Chemotherapy is standard, but investigational TKIs that are selective for HER2 exon 20, including poziotinib, pyrotinib, and mobocertinib, are an exciting option. Although the ORR surpassed 50% in one phase II study of pyrotinib, the PFS for drugs in this group tends to be lower than 6 months.
The Role of TKIs in BRAF-Mutated NSCLC
David Planchard, MD, PhD
BRAF mutations are associated with poorer prognosis and are difficult to diagnose clinically, so those with advanced lung adenocarcinoma should undergo molecular profiling with PCR or NGS, Dr. Planchard said.
He focused on V600 mutations, which are more common than non-V600 BRAF alterations and far more targetable. Unlike the others, V600 mutations do not co-exist with RAS alterations; they affect more never-smokers, are less likely to cause brain metastases, and have a better prognosis.
If a BRAF V600E mutation is discovered before treatment, first-line therapy can consist of either platinum-based chemotherapy or a combination of the approved selective TKIs dabrafenib and trametinib. The combination works better than TKI monotherapy because it blocks treatment resistance through MEK1 and MEK2 activation and reduces the risk of cutaneous squamous cell carcinoma, Dr. Planchard said. Dabrafenib/trametinib also shows promise in non-V600 BRAF mutations that are kinase-activated, RAS-dependent BRAF dimers, and for patients with other subtypes of NSCLC who acquire a BRAF V600 mutation during treatment.
Although asthenia, among other side effects, can arise as an adverse event, Dr. Planchard said, therapy can continue with a dabrafenib dose reduction.
Resistance in patients with BRAF V600 mutations can involve NRAS, COT, CRAF, MEK, BRAF, RTK, or PI3K/AKT pathway alterations. Pan-RAF inhibitors and paradox breakers—developed to inhibit the V600 mutation without causing paradoxical MAPK pathway activation—are being investigated to target these changes. The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib (each approved to treat BRAF mutations in other cancer types) is being investigated in a phase II trial.
For more, this lecture and other ELCC 2022 presentations are available on-demand for attendees on OncologyPro.
