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Professor of Medicine
Director, Division of Medical Oncology
Department of Medicine
Los Angeles, California
Karen L. Reckamp, MD, MS, has disclosed that she has received consulting fees from AstraZeneca, Boehringer Ingelheim, Calithera, Genentech, Guardant, Precision Health, and Tesaro and funds for research support paid to her prior institution from AbbVie, Acea, Adaptimmune, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Guardant, Janssen, Loxo Oncology, Molecular Partners, Seattle Genetics, Spectrum, Takeda, Xcovery, and Zeno.
Recent advances in targeted therapies have equipped medical oncologists with highly effective, well-tolerated treatments and underscored the importance of screening patients who are newly diagnosed with non-small-cell lung cancer (NSCLC) for all oncogenic driver mutations with available therapies. Among the newest approvals in targeted therapies are selective RET inhibitors, selpercatinib and pralsetinib, which are approved for any line of therapy in adults with metastatic RET fusion–positive NSCLC. Here, I discuss a patient case from my practice to explore how to incorporate RET inhibitors into practice.
Case: Patient With RET Fusion–Positive, PD-L1–High Lung Adenocarcinoma
The patient is a 43‑year‑old female nonsmoker with newly diagnosed adenocarcinoma of the lung who originally presented with progressive cough and dyspnea. A chest X‑ray at the time showed a right pleural effusion and some right lung consolidation, and she was initially given antibiotics. However, during the following month, she noted some growth of masses in her right neck, and a follow-up chest X‑ray showed the right pleural effusion persisted and there was a more definitive right lower lobe mass in addition to the new palpable neck nodules. She had a CT of the neck and chest that demonstrated a right lower lobe consolidation with some nodular infiltrates in the right lung and a moderate right pleural effusion, with left supraclavicular and right cervical lymphadenopathy.
Cytology findings from a thoracentesis sample demonstrated an adenocarcinoma that was TTF‑1 and napsin A positive, and PD-L1 expression was 75% by IHC. Next-generation sequencing (NGS) revealed a KIF5B‑RET fusion, a TP53 mutation, low TMB, and no MSI.
She subsequently underwent PET/CT, which showed multiple hypermetabolic masses in the right lung and lymph nodes and right pleural metastases. In addition, there was hypermetabolic activity in the left supraclavicular region and right cervical lymph nodes. An MRI of the brain demonstrated lesions in the right parietal (0.5 cm) and left frontal (0.4 cm) regions, and this was consistent with metastatic disease. Ultimately, her staging was a clinical T2BN2M1C.
Choice of Therapy for Newly Diagnosed RET Fusion–Positive NSCLC Prior to New RET Inhibitor Approval
Treatment for this patient began before the approval of the selective RET inhibitors selpercatinib and pralsetinib, which now that they are approved, would be my first-line therapy of choice for a patient with newly diagnosed RET fusion–positive NSCLC. However, at the time, the available first-line options included off-label use of a multitargeted TKI (most commonly cabozantinib), chemotherapy, or chemoimmunotherapy. The multitargeted TKIs have lower response rates than other targeted agents, up to approximately 40%, and significant toxicity due to having multiple targets and off-target side effects; thus, rather than one of these TKIs, we typically would give these patients first-line chemotherapy or chemoimmunotherapy.
Because this patient had high PD-L1 expression at 75%, she was also a candidate for single-agent pembrolizumab, but we decided against this option based on data from the IMMUNOTARGET study evaluating immune checkpoint inhibition across patients with advanced NSCLC harboring at least 1 actionable mutation. In IMMUNOTARGET, patients with RET fusion–positive NSCLC, albeit a small population, were shown to have limited responses to single‑agent checkpoint inhibitor therapy. Clinical experience also confirms that patients who are light or never‑smokers, such as this patient, tend to have less robust responses with single‑agent checkpoint inhibitor therapy.
After discussion with the patient, we selected chemoimmunotherapy with carboplatin and pemetrexed plus pembrolizumab, a decision that was supported by the fact that this patient would have met enrollment criteria for the phase III KEYNOTE‑189 study comparing pembrolizumab plus standard platinum-based chemotherapy vs chemotherapy alone.
The patient first underwent stereotactic radiosurgery (SRS) to the brain and had responses in those lesions, then received 4 cycles of carboplatin, pemetrexed, and pembrolizumab and had an excellent response in the lung and lymph nodes. She continued on maintenance pemetrexed and pembrolizumab for a year until she developed increased dyspnea and was found to have recurrent right pleural effusion and growth in the left supraclavicular lymph node. A repeat MRI of the brain identified a new right frontal lobe lesion (0.7 cm) that was asymptomatic.
Second-line RET Inhibition After Disease Progression on First-line Chemoimmunotherapy
By the time our patient experienced disease progression on first-line chemoimmunotherapy, selpercatinib had been approved based on data from the open-label phase I/II LIBRETTO-001 study showing an ORR of 65% among platinum-experienced patients and 85% among treatment-naive patients with advanced or metastatic NSCLC harboring RET fusions, along with an intracranial response rate of 91% among patients with brain lesions.
Thus, we started her on selpercatinib. We also discussed a second SRS to the brain, but due to the high CNS penetration and intracranial activity seen with selpercatinib, and because her CNS metastases were asymptomatic, we decided to forego this treatment. In fact, if she had presented after selpercatinib was approved and we had started it as first-line therapy, she may have been able to avoid upfront SRS and instead proceeded with routine monitoring of her brain.
To date, the patient has tolerated treatment with selpercatinib well and remains on treatment. Initially, she had mild elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (grade 1), but those levels normalized without treatment interruption. She also has had some intermittent diarrhea that has been controlled with loperamide. She now has subsequently developed hypertension and has started treatment with amlodipine, with improvement in her blood pressure.
Clinical Considerations for Use of Selective RET Inhibitors
As we incorporate selective RET inhibitors into practice, there are some key considerations for patient care, including toxicity management, patient monitoring, and how to treat patients with progressive disease after RET inhibition.
Overall, new selective RET inhibitors have been very well tolerated. In clinical trials, both selpercatinib and pralsetinib have demonstrated low rates of grade ≥ 3 treatment-related adverse events. The most common adverse events were laboratory abnormalities, including increases in AST, ALT, and creatinine. GI toxicities were also common, including diarrhea, constipation, and nausea. Some patients experienced peripheral edema or hypertension, which are on‑target toxicities seen across this drug class.
For mild (grade 1) laboratory abnormalities, patients should be monitored, but no dose reduction or interruption is required. However, if lab abnormalities reach grade 2, RET inhibitor dosing should be withheld until resolution of the adverse event, and for grade 3, the dose should be reduced. As most GI toxicities are low grade, they can be managed with over-the-counter medications. Similarly, hypertension can be managed with standard prescription medications.
Patients receiving selective RET inhibitors should be monitored closely, including laboratory and blood pressure screenings, during the first few months of therapy. Of importance, hypertension does not necessarily occur immediately upon initiating treatment; it can happen even after a few months, so it is important to watch for that. We should also discuss potential GI toxicities with our patients to make sure they are reporting any symptoms. Once patients are on a stable dose and have had stable labs, then we can consider extending monitoring to every 3 months. This is especially beneficial in the era of COVID‑19, when fewer in‑person visits reduce the risks for all.
Treatment Following Disease Progression on Selective RET Inhibitors
For patients who progress on selective RET inhibitor therapy, choice of subsequent therapy will depend on their overall treatment history. For a patient who received first-line selpercatinib, my first choice in the second-line setting would be cytotoxic therapy with immune checkpoint inhibitor therapy—this is the inverse to the therapy sequence received by our patient. However, if a patient who received chemoimmunotherapy in the first-line setting were to progress while receiving second-line selpercatinib, like our patient, the standard-of-care third‑line therapy would be docetaxel or docetaxel/ramucirumab. Moving forward, it will be important to understand the mechanisms of resistance to RET inhibition. There are specific solvent front mutations that do occur with these agents, and next-generation RET inhibitors (eg, RET/SRC inhibitor TPX-0046) are being developed to try to overcome these mechanisms of resistance.
To summarize, the new selective RET inhibitors are well tolerated, potent, and highly active in the brain—key features we seek in any targeted therapy to an oncogenic driver. In addition to selpercatinib, pralsetinib recently received approval by the FDA in this setting based on results from the open-label phase I/II ARROW trial demonstrating an ORR of 61% among platinum-experienced patients and 73% among treatment-naive patients with advanced or metastatic RET fusion–positive NSCLC, with 56% of patients with brain metastases showing an intracranial response.
The key now will be to identify patients with RET fusion–positive NSCLC in whom to use these highly effective therapies. A recent population‑based analysis of Surveillance, Epidemiology, and End Results data offered compelling evidence that patients with NSCLC are living longer based on targeted therapy approvals. Considering that we now have 7 oncogenic drivers with FDA-approved targeted therapies, we need to use broad-spectrum NGS to screen all patients, so that we do not miss those with these potentially life‑changing targetable alterations.
To receive management recommendations from a panel of 5 lung cancer experts for a wide variety of patient presentations, click here to use CCO’s Interactive Decision Support Tool: Expert Insight on Therapy Selection for Unresectable Stage III and Metastatic NSCLC. For easy access to this and several other patient management tools from CCO, download the CCO Decision Support app from the app store on your phone!
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