Targeted Therapy for Mutation-Driven Metastatic Non–Small-Cell Lung Cancer: Considerations for ALK-Rearranged Tumors

April 15, 2019

In this article, important concepts in the molecular testing of non–small-cell lung cancer are highlighted.

The Case

A 64-year-old man ultimately diagnosed with ALK-rearranged non–small-cell lung cancer (NSCLC) with brain metastases initially presents to the emergency department with progressive dyspnea, a non-productive cough, and weight loss. His past medical history includes chronic obstructive pulmonary disease, nonalcoholic steatohepatitis, and non–insulin-dependent diabetes; he also has a 33 pack-year history of tobacco use, although he quit smoking 15 years prior to diagnosis. A chest x-ray is obtained, revealing questionable findings in the right hilum and a large right pleural effusion. A CT scan of the chest without contrast confirms right lung atelectasis, a large right pleural effusion, right lower lobe necrosis, and right hilar fullness.

Therapeutic and diagnostic thoracentesis was completed, with cytology positive for adenocarcinoma of the lung (thyroid transcription factor 1–positive, cytokeratin (CK)7-positive, CK20-negative, presence of WT-1, and calretinin-negative). Expression of programmed death ligand 1 (PD-L1) was 50%. ALK rearrangement was negative by fluorescence in situ hybridization (FISH) testing. The EGFR, ROS1, and BRAF genes were all wild-type. Due to rapidly reaccumulating symptomatic pleural effusion, video-assisted thoracoscopic surgery with right pleural tissue biopsy and talc pleurodesis were completed.

Pleural tissue was sent for pathology review and was once again consistent with adenocarcinoma of the lung. However, PD-L1 expression was 0%, and ALK rearrangement by immunohistochemistry was positive. ALK testing was repeated on this tissue sample with FISH (via the US Food and Drug Administration [FDA]–approved Vysis ALK Break Apart FISH Probe Kit), which detected the ALK (2p23) rearrangement in 52% of the cells analyzed.

Completion staging imaging was obtained, including a PET/CT scan and brain MRI with and without contrast. The PET/CT scan demonstrated a hypermetabolic lesion in the posterior right lower lobe, extensive hypermetabolic pleural-based disease in the right hemithorax with hypermetabolic right hilar and subcarinal lymph nodes, as well as lymph nodes at the left mediastinum and left neck base. Multiple foci of osseous metastases were visible, as was a possible small lesion in the left liver. Brain MRI revealed 3 metastatic lesions: a 12-mm lesion in the right caudate nucleus, a 10-mm lesion in the right temporal lobe, and a 3-mm lesion in the left cerebellar hemisphere.

The patient experienced an ongoing non-productive cough, dyspnea on exertion, right pleuritic pain, and back pain. He consulted with a radiation oncologist and received stereotactic radiosurgery to the right temporal lobe lesion (21 Gy) and the right parietal lobe lesion (21 Gy). The 3-mm lesion was not treated with radiation. First-line systemic treatment was initiated with 600-mg oral alectinib twice daily, which was well tolerated with no significant treatment-related toxicities. The patient’s disease-related symptoms improved. Imaging was repeated 6 weeks later. A brain MRI with and without contrast revealed a complete response in all 3 lesions, including the 3-mm lesion that was not initially treated with radiation. A CT scan of the chest/abdomen/pelvis with contrast exhibited a significant radiographic response in all previously identified sites of disease.

Treatment Considerations for ALK-Rearranged Metastatic NSCLC

The scope of treatment for ALK-rearranged metastatic NSCLC has substantially evolved since the initial identification of this aberration. Although ALK+ metastatic NSCLC represents just 3% to 5% of all NSCLC cases, there are now five FDA-approved targeted therapies in this space. Crizotinib was the first-in-class therapeutic intervention against the driver alteration; its benefits were first confirmed in the PROFILE 1014 study.[1] However, since crizotinib is an ALK/ROS1/MET inhibitor, patients treated with this agent relapse, and the more potent and brain-penetrable next-generation ALK inhibitors have surpassed crizotinib in both efficacy and tolerability. While alectinib, ceritinib, and crizotinib are all FDA-approved as first-line and subsequent-line therapies, brigatinib and lorlatinib are approved for use as only subsequent-line treatment. The National Comprehensive Cancer Network guidelines recommend alectinib-a highly selective central nervous system (CNS)-active ALK inhibitor-as the preferred first-line therapy for ALK-rearranged metastatic NSCLC.[2]

Rationale Behind Targeted Therapy With Alectinib

The global phase III ALEX study compared alectinib with crizotinib in the first-line treatment of ALK+ metastatic NSCLC. The primary analysis showed a significant improvement in the study’s primary endpoint, median progression-free survival (PFS), with alectinib,[3] leading to its FDA approval in the first-line setting. In this patient’s case, first-line targeted therapy with alectinib was chosen based on the results of this trial. Moreover, the efficacy of alectinib in the CNS limited the need for whole-brain irradiation in the setting of few, small, and asymptomatic brain metastases.

At the 2018 American Society of Clinical Oncology Annual Meeting, the ALEX study was updated with 10 months of additional follow-up data.[4] Among the findings were an unprecedented investigator-assessed median PFS of 34.8 months and an updated hazard ratio (HR) of 0.43. The duration of treatment was also longer. In addition, the depth of response was deeper: > 40% of responders treated with alectinib demonstrated > 75% tumor reduction compared with ~25% of responders treated with crizotinib. Rates of significant adverse events were lower, and subsequent dose adjustments and treatment discontinuations were fewer. Notably, among the 303 patients included in this analysis, about 40% in each arm had baseline CNS metastases; 122 patients harbored baseline CNS metastases (alectinib arm, n = 64; crizotinib arm, n = 58), and 43 harbored measurable lesions (alectinib arm, n = 21; crizotinib arm, n = 22). In addition, 46 patients had received prior radiotherapy (alectinib arm, n = 25; crizotinib arm, n = 21).[4]

PFS with alectinib was comparable between patients with baseline CNS metastases (HR, 0.40; 95% CI, 0.25–0.64) and those without CNS metastases (HR, 0.51; 95% CI, 0.33–0.80), despite prior radiotherapy status. Time to CNS progression was significantly longer with alectinib vs crizotinib and was similar to that of patients with and without baseline CNS metastases (P < .0001). In patients who were administered prior radiotherapy, the CNS objective response rate (ORR) was 85.7% with alectinib vs 71.4% with crizotinib. Among those who had not been administered previous radiotherapy, the ORR was 78.6% for alectinib vs 40.0% for crizotinib.[4]

Of high significance, the endpoints in the ALEX trial were also assessed based on CNS involvement. The median PFS, duration of response, and depth of response were all upheld regardless of baseline CNS metastases.[4] For patients with small and asymptomatic brain metastases in the setting of ALK-rearranged NSCLC, there is an opportunity to defer whole-brain irradiation until intracranial response to alectinib is assessed radiographically. With alectinib assuming this clear position as the first-line treatment for ALK+ metastatic NSCLC, it will become even more important to understand ALK resistance patterns and appropriate drug sequencing when a patient progresses on alectinib.[3,4]

Forgoing Immune Checkpoint Therapy

The decision not to administer immunotherapy was based on previous research involving EGFR/ALK-mutated metastatic NSCLC with characteristics similar to the patient in this current case study, whose tumor harbored an ALK rearrangement. Trials of second-line or later treatments for metastatic NSCLC have shown that patients with EGFR-mutant tumors do not benefit from checkpoint inhibitors. This seems to be the case regardless of PD-L1 expression. In a meta-analysis,[5] Lee et al found that, in patients with driver mutations, immune checkpoint inhibitors do not lengthen overall survival (OS) any more than docetaxel. The three studies included in this meta-analysis compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) vs docetaxel (n = 776). In the overall population, immune checkpoint inhibitors resulted in longer OS compared with docetaxel (n = 1,903; HR, 0.68; 95% CI, 0.61–0.77; P < .0001). The same benefit was seen in the EGFR wild-type subgroup (n = 1,362; HR, 0.66; 95% CI, 0.58–0.76; P < .0001). However, in the EGFR-mutant subgroup, no increase in OS was observed (n = 186; HR, 1.05; 95% CI, 0.70–1.55; P < .81).[5]

The patient in this case study had a PD-L1 tumor proportion score (TPS) of 50% on pleural fluid but 0% on pleural tissue. In an abstract,[6] Hui et al showed that, among patients with a PD-L1 TPS higher than 50% treated with pembrolizumab, those with EGFR-mutant tumors had significantly reduced OS vs those with EGFR wild-type tumors (median OS, 6.5 vs 15.7 months). Furthermore, OS did not change significantly based on PD-L1 expression in the EGFR-mutant group (TPS, > 50% vs < 1%; median OS, 6.5 vs 5.7 months). In the EGFR wild-type subgroup, however, a difference was observed (TPS > 50% vs < 1%; median OS, 15.7 vs 9.1 months). Notably, the patient’s tumor in this case study had an ALK rearrangement-not an EGFR mutation. However, similar results have been demonstrated for both and are anticipated regardless of the driver mutation (ie, EGFR or ALK).[6]

In a retrospective study,[7] Gainor et al found that NSCLC tumors possessing EGFR mutations or ALK rearrangements are significantly linked to lower ORR values when treated with programmed death 1 (PD-1)/PD-L1 inhibitors. The authors observed objective responses in only 1 of 28 EGFR/ALK-mutant patients (3.6%) vs 7 of 30 EGFR/ALK wild-type patients (23.3%; P = .053). Additionally, the ORR among never- or light-smokers (≤ 10 pack-years) was 4.2% vs 20.6% among heavy smokers (P = .123). Not only did the patient in the current case study have ALK-rearranged NSCLC, he would also be considered a heavy smoker per these cutoffs in pack-years, with a lower ORR in response to PD-1/PD-L1 inhibitors.[7]


Although immunotherapy has significantly impacted the treatment of metastatic NSCLC, regardless of the PD-L1 TPS, treatment with immunotherapy is not prioritized over targeted therapy in the first-line treatment of tumors with EGFR or ALK driver mutations. When a driver mutation is identified in metastatic NSCLC, such as the ALK rearrangement seen in this case study, targeted therapy provides the best outcomes on multiple levels. In an era of immune checkpoint inhibition, it is important to remember that the driver mutation-not the PD-L1 expression-determines first-line treatment. The benefit of agents penetrating the CNS is important, since it may provide alternatives to whole-brain irradiation, which has potentially unwanted toxicities.

Financial Disclosure:Dr. Mileham is on the speakers’ bureau for Merck. Dr. Ahmad and Dr. Kim have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


Using Molecular Testing to Alter Treatment in Favor of Positive Patient Outcomes

Steven Powell, MD

In this article, Mileham et al highlight important concepts in the molecular testing of non–small-cell lung cancer (NSCLC). Specifically, the case study they present demonstrates the finding of discordance in molecular testing based on the tissue specimen. While the cytology sample showed programmed death ligand 1 (PD-L1) positivity, the core biopsy did not. More importantly, ALK fusion testing was negative in the initial cytology specimen, yet was found to be positive in the core biopsy.

For the practicing oncologist, this is extremely important to consider because tissue biopsies can often be difficult to obtain and may require additional procedures. The additional finding of the ALK fusion after repeat biopsy further highlights the importance of adequate tissue sampling. The therapy selected in this case (alectinib) was significantly different than what would have previously been considered (pembrolizumab) and led to a favorable outcome for the patient. In the end, this case supports the role of obtaining appropriate testing on the correct tissue specimens in order to help guide first-line therapy for NSCLC.

Financial Disclosure: Dr. Powell has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Dr. Powell is a Hematologist/Oncologist at Sanford Cancer Center; an Assistant Scientist at the Cancer Biology Center at Sanford Research; and an Assistant Professor of Internal Medicine at the University of South Dakota’s Sanford School of Medicine, Sioux Falls, South Dakota.



1. Solomon BJ, Cappuzzo F, Felip E, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016;34:2858-65.

2. National Comprehensive Cancer Network guidelines. Non-small cell lung cancer. Accessed March 21, 2019.

3. Peters S, Camidge DR, Shaw AT, et al; ALEX trial investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829-38.

4. Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2018;15(suppl):abstr 9043.

5. Lee CK, Man J, Lord S, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-A meta-analysis. J Thorac Oncol. 2017;12:403-7.

6. Hui R, Gandhi L, Cost EC, et al. Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab (pembro). J Clin Oncol. 2016;15(suppl):abstr 9026.

7. Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A restrospective analysis. Clin Cancer Res. 2016;22:18.

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