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Biomarker Testing in Patients With Solid Tumors: Interactive Case Challenge for NSCLC
Nurse Practitioners/Nurses: 0.50 Nursing contact hours, includes 0.50 hour of pharmacotherapy credit
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Released: June 16, 2026
Expiration: December 15, 2026
Activity
Case Follow-up 2 and Case Conclusion
After reviewing the molecular profile, the oncology team explains that the ALK rearrangement is now the most important finding for systemic treatment selection. Because he remains neurologically stable and can take oral therapy, the patient elects to transition from this initial bridging chemotherapy plan to first-line ALK-directed treatment after a shared decision-making discussion that includes both alectinib and lorlatinib as options.
The patient starts lorlatinib and is counseled that it may be taken with or without food and that new or worsening confusion, memory problems, mood or speech changes, seizures, dizziness, fainting, abnormal heartbeat, shortness of breath, cough, swelling, numbness or tingling, or symptoms of high blood sugar should be reported promptly to the care team. You may also review with the patient a need for ongoing monitoring of liver enzymes, creatine phosphokinase, heart rate, and CNS symptoms.
At the next follow-up, cough and dyspnea are improved, no new neurologic symptoms are reported, and repeat brain imaging shows no new CNS lesions—stable disease. The patient and his spouse now understand that, although pembrolizumab-based therapy was initially considered because of the high PD-L1 result (50%) and urgent symptoms, the identification of an actionable ALK gene rearrangement appropriately redirected treatment toward biomarker-matched therapy.
Key Research and Case Summary
In our first case, a 68-year-old patient presented with newly diagnosed stage IV lung adenocarcinoma and minimal remote smoking history in college. Her tumor had PD-L1 expression of 10%, but broad molecular testing via NGS was still pending.
Although PD-L1 status was available, the optimal first step was to wait for the full molecular/NGS report before starting first-line systemic therapy because actionable driver alterations can often determine the preferred initial treatment approach in advanced nonsquamous NSCLC.3 Broad molecular testing is recommended in metastatic or advanced NSCLC, and PD-L1 positivity alone should not drive immediate chemoimmunotherapy treatment decisions when a clinically stable patient may have a targetable driver alteration.6,8,9
Approximately 2 weeks later, the patient's NGS report identified an actionable EGFR exon 19 deletion, supporting initiation of EGFR-directed oral therapy.10 For patients with EGFR-mutated metastatic NSCLC, current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) recommendations support EGFR-directed therapy as a preferred first-line strategy, and osimertinib is indicated for first-line treatment in adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.6,7,10 Alternative standard-of-care first-line options for these patients include osimertinib plus platinum-based chemotherapy, as evaluated in the FLAURA2 trial, and amivantamab plus lazertinib, as evaluated in the MARIPOSA trial.10,21-23
In the phase III FLAURA trial, first-line osimertinib improved PFS vs gefitinib or erlotinib, with a median PFS of 18.9 vs 10.2 months (HR: 0.46; 95% CI: 0.37-0.57; P <.001), and median overall survival (OS) of 38.6 vs 31.8 months (HR: 0.80; 95.05% CI: 0.64-1.00; P = .046) in patients with metastatic EGFR exon 19 deletion NSCLC.10,20,23
More recently, in the phase III FLAURA2 trial, first-line osimertinib plus platinum-pemetrexed chemotherapy improved PFS vs osimertinib monotherapy, with a median PFS of 25.5 vs 16.7 months (HR: 0.62; 95% CI: 0.49-0.79; P <.001), and median OS of 47.5 vs 37.6 months (HR: 0.77; 95% CI: 0.61-0.96; P = .02) in patients with previously untreated EGFR exon 19 deletion or exon 21 L858R mutation–positive advanced NSCLC.21,24 Similarly, in the phase III MARIPOSA trial, first-line amivantamab plus lazertinib improved PFS vs osimertinib, with a median PFS of 23.7 vs 16.6 months (HR: 0.70; 95% CI: 0.58-0.85; P <.001), and improved OS at final analysis, with median OS not estimable vs 36.7 months (HR: 0.75; 95% CI: 0.61-0.92; P = .005) in patients with previously untreated EGFR exon 19 deletion or exon 21 L858R mutation–positive advanced NSCLC.22,25
Starting chemoimmunotherapy before EGFR exon 19 deletion results were known could have led the patient to experience severe side effects due to earlier immunotherapy use when transitioning to targeted oral therapy with osimertinib.26 Because of this, it is strongly recommended to wait for molecular results before starting therapy when the patient is clinically stable.
After osimertinib tablets are received and the patient starts taking them, the next key step is to ascertain whether the patient understands how to take the medication correctly. Because oral EGFR-directed therapy is self-administered at home, oncology care providers (including nurse practitioners or physician associates) should help confirm medication access, dosing routine, missed-dose handling, AEs, disease symptoms, and laboratory monitoring early in the treatment course. The optimal communication strategy used for our patient case was to ask: “How are you taking your EGFR-targeted medication?” This open-ended question allows the patient to describe her routine in her own words and may identify medication-use errors or misunderstandings that might be missed with yes/no adherence-type questions.10,27
Another key patient–oncology team interaction that may require biomarker retesting and evaluation occurs when the patient's disease progresses. In case 1, routine imaging after approximately 2 years of oral EGFR-directed therapy showed asymptomatic progression with new liver metastases, shifting the clinical question to evaluation of acquired resistance.11,12 The most informative next step is to obtain tissue from a progressing lesion when feasible and send a concurrent liquid biopsy, because tissue can assess for histologic transformation, including small cell transformation, and plasma-based testing can help identify acquired molecular resistance mechanisms that may guide next-line therapy. Liquid biopsy alone is incomplete when histologic transformation is a concern, and changing treatment without reassessment may miss clinically relevant findings such as transformation or targetable resistance alterations that could change management.13
Clinical Implications
Overall, patient case 1 highlights 3 practical takeaways for advanced practice providers caring for patients with metastatic NSCLC: complete broad molecular testing before first-line treatment selection when the patient is clinically stable; use open-ended questioning to confirm how patients are taking oral targeted therapy; and reassess progression after EGFR-directed therapy with tissue biopsy when feasible, plus liquid biopsy as a complementary tool to evaluate acquired resistance.6,8,11,27
In our second case, a 75-year-old patient presented with metastatic lung adenocarcinoma, substantial symptom burden, and PD-L1 expression of 50%, with liver and brain metastases.
Because broad-panel NGS was still pending but treatment could not reasonably wait, beginning platinum-based chemotherapy while deferring immunotherapy was a practical bridge strategy. In symptomatic metastatic nonsquamous NSCLC, immune checkpoint inhibitor (ICI)–based therapy is an established option when no EGFR or ALK genomic tumor aberration is present, but pending driver testing remains critical because the molecular result may change the preferred first-line approach.7-9,15,28
Several ICI-based approaches are approved for selected patients with newly diagnosed advanced NSCLC, including monotherapy, chemoimmunotherapy, and dual immuno-oncology therapy, depending on biomarker status and clinical context.3
When this patient's tissue-based NGS results returned, they identified an EML4-ALK rearrangement with KRAS wild-type, EGFR wild-type, and ROS1-negative disease. That actionable result changes the preferred first-line strategy. Current ASCO and ESMO living guidance supports biomarker-directed systemic treatment for metastatic ALK-positive NSCLC, including in patients with CNS disease, so PD-L1 expression should no longer determine the ongoing systemic plan once the ALK result is known.7,28
Available ALK Inhibitors
Alectinib is FDA approved for adult patients with ALK-positive metastatic NSCLC detected by an FDA-approved test. In the phase III ALEX trial, alectinib improved independent review committee–assessed PFS vs crizotinib, with median PFS of 25.7 vs 10.4 months (HR: 0.53; 95% CI: 0.38-0.73); the objective response rate (ORR) was 79% vs 72%, respectively. Among patients with measurable CNS lesions at baseline, intracranial ORR was 81% with alectinib vs 50% with crizotinib.29 In the updated ALEX analysis reported by Mok and colleagues, median PFS was 34.8 vs 10.9 months and 5-year OS was 62.5% vs 45.5% with alectinib vs crizotinib, respectively.30 Key AEs with alectinib include hepatotoxicity, constipation, fatigue, myalgia, edema, rash, and cough; hepatotoxicity occurred in 41% of patients, with grade 3 or higher hepatotoxicity in 8%.29
Brigatinib is FDA approved for adult patients with ALK-positive metastatic NSCLC detected by an FDA-approved test.31 In the phase III ALTA 1L trial, first-line brigatinib improved blinded independent central review (BICR)–assessed PFS vs crizotinib, with median PFS of 24.0 vs 11.0 months (HR: 0.49; 95% CI: 0.35-0.68; P <.0001); the confirmed ORR was 74% vs 62%, respectively.31,32 Among patients with measurable CNS metastases at baseline, intracranial ORR was 78% with brigatinib vs 26% with crizotinib. Key AEs with brigatinib include diarrhea, rash, cough, hypertension, fatigue, nausea, myalgia, dyspnea, abdominal pain, and headache; the label also highlights monitoring for interstitial lung disease (ILD)/pneumonitis, hypertension, bradycardia, visual disturbance, CPK elevation, pancreatic enzyme elevation, hepatotoxicity, hyperglycemia, photosensitivity, and embryo-fetal toxicity.31
Ceritinib is FDA approved for adult patients with metastatic ALK-positive NSCLC detected by an FDA-approved test.33 In the phase III ASCEND-4 trial, first-line ceritinib improved BICR-assessed PFS vs platinum-pemetrexed chemotherapy, with median PFS of 16.6 vs 8.1 months (HR: 0.55; 95% CI: 0.42-0.73; P <.0001); the ORR was 73% vs 27%, respectively.33,34 Among patients with measurable CNS lesions at baseline, intracranial ORR was 57% with ceritinib vs 22% with chemotherapy. Key AEs with ceritinib taken at the recommended dose of 450 mg with food include gastrointestinal toxicity, with diarrhea, nausea, and vomiting reported in 59%, 43%, and 38% of patients, respectively. The label also highlights monitoring for hepatotoxicity, ILD/pneumonitis, QT prolongation, hyperglycemia, bradycardia, and pancreatitis. Key AEs with ceritinib include diarrhea, nausea, abdominal pain, vomiting, and fatigue; gastrointestinal adverse reactions occurred in 79% of patients treated with the recommended dose of 450 mg with food, with grade 3 diarrhea and grade 3 vomiting each reported in 0.9% of patients.33
Crizotinib is FDA approved for adult patients with metastatic NSCLC whose tumors are ALK- or ROS1-positive as detected by an FDA-approved test.17 In the phase III PROFILE 1014 trial, first-line crizotinib improved independent radiology review–assessed PFS vs platinum-pemetrexed chemotherapy, with median PFS of 10.9 vs 7.0 months (HR: 0.45; 95% CI: 0.35-0.60; P <.001); the ORR was 74% vs 45%, respectively.17,35 Crizotinib is an ALK-directed option, but its role is limited in patients with brain metastases compared with newer ALK inhibitors that have stronger CNS activity. Key AEs with crizotinib include vision disorders, diarrhea, nausea, edema, vomiting, and constipation, reported in 71%, 61%, 56%, 49%, 46%, and 43% of patients, respectively. The label also highlights monitoring for hepatotoxicity, ILD/pneumonitis, QT prolongation, bradycardia, and severe visual loss.17
Ensartinib is FDA approved for adult patients with ALK-positive locally advanced or metastatic NSCLC detected by an FDA-approved test who have not previously received an ALK inhibitor.36 In the phase III eXALT3 trial, ensartinib improved BICR-assessed PFS vs crizotinib, with median PFS of 25.8 vs 12.7 months (HR: 0.56; 95% CI: 0.40-0.79; P = .0008); the ORR was 74% vs 67%, respectively.36,37 Among patients with measurable CNS disease at baseline, CNS ORR was 59% with ensartinib vs 21% with crizotinib. Key AEs with ensartinib include rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, pyrexia, and fatigue; rash occurred in 66% of patients, with grade 3/4 rash in 12%.36
Lorlatinib is also FDA approved for adult patients with metastatic ALK-positive NSCLC detected by an FDA-approved test.16 In the phase III CROWN trial, lorlatinib improved PFS vs crizotinib in previously untreated ALK-positive metastatic NSCLC, with median PFS not reached vs 9.3 months (HR: 0.28; 95% CI: 0.19-0.41) and ORR rate 76% vs 58%, respectively.16,18 Of importance, among patients with measurable brain metastases at baseline, the intracranial response rate was 82% with lorlatinib vs 23% with crizotinib, with complete intracranial response in 71% vs 8%, respectively.16
At the ASCO 2026 annual meeting, in the 7-year CROWN update, median PFS remained not reached with lorlatinib vs 9.1 months with crizotinib (HR: 0.19; 95% CI: 0.13-0.26), with 7-year PFS rates of 55% vs 3%, respectively.4 Median time to intracranial progression was also not reached with lorlatinib vs 16.4 months with crizotinib (HR: 0.06; 95% CI: 0.03-0.12), and no new intracranial progression events were reported after 30 months on lorlatinib. Key AEs with lorlatinib include edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, and cough; grade 3/4 hypercholesterolemia and hypertriglyceridemia each occurred in 21% of patients.16
Clinical Implications
This case highlights 3 practical points for advanced practice providers caring for patients with metastatic ALK-positive NSCLC. First, even in a symptomatic patient with high PD-L1 expression, broad molecular profiling remains essential because identification of an ALK rearrangement can fundamentally redirect first-line treatment selection. Second, when treatment cannot wait, and NGS is still pending, a short course of platinum-based chemotherapy can serve as a pragmatic bridge, but ICIs should generally be deferred until EGFR and ALK results are known. Third, once an ALK rearrangement is identified, the clinical discussion should shift to first-line ALK-directed therapy, with agents such as alectinib or lorlatinib being particularly relevant when durable systemic control and intracranial activity are priorities, as illustrated by the data summaries above.