Posted: Friday, August 18, 2017
Targeting a Fusion Oncogene: EML4-ALK
A small group of patients with advanced non–small cell lung cancer (NSCLC) have tumors that are associated with an inversion in chromosome 2 [the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene is juxtaposed with the 3' end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK].1 Crizotinib is an oral tyrosine kinase inhibitor (TKI) used to treat those patients whose tumors are thought to arise from an ALK rearrangement (eg, EML4-ALK) as well as those whose tumors are positive for a related oncogene, ROS1.2 Clinically, NSCLC is often diagnosed in these patients at younger ages than is typical for those with lung cancer. Moreover, many of these patients are never smokers or have a light smoking history and have adenocarcinoma with signet ring or acinar histology.3 Of note, ALK arrangements are usually mutually exclusive with epidermal growth factor receptor (EGFR) mutations, KRAS mutations, or ROS1 rearrangements.4,5
Waiting Is the Hardest Part
In 2017, most oncologists and cancer centers request routine testing of multiple markers—including EGFR mutation status, ALK rearrangements, and ROS1 rearrangements—at the time of diagnosis of metastatic NSCLC.7 The results of those tests may not be available for as long as 2 to 3 weeks, although it depends on the process at each institution. Acknowledging the patient’s anxiety during the waiting period, as well as the fact that some patients are quite ill and symptomatic before treatment, Alice T. Shaw, MD, PhD, Director of the Center for Thoracic Cancers at Massachusetts General Hospital and Associate Professor of Medicine, Harvard Medical School, Boston, noted, “We try to obtain the ALK results within a week, but at many centers, the results can take 1 to 3 weeks.” Dr. Shaw said that the waiting can be a challenge for patients because of the emotional component related to having to wait for results before a treatment decision can be made. Once the results are available, the treatment decision is quite straightforward because responses with (TKI) therapy in patients with these ALK- or ROS1-positive tumors are often robust.8
Why Not Immunotherapy?
Although patients may ask about immunotherapy, multiple clinical trials suggest that never smokers—many of whom have either ALK rearrangements or EGFR mutations—benefit least from the checkpoint inhibitors,9-11 Dr. Shaw pointed out. In contrast, they can derive substantial benefit from the appropriate TKIs and even chemotherapy, compared with immunotherapy. “Sometimes patients ask about whether they can add immunotherapy to crizotinib. It is unclear whether there would be added benefit, but there would likely be added toxicity. I would definitely not do this outside of a clinical trial.” [Editor’s Note: Some of these approaches are being investigated.12]
With regard to patient questions about checkpoint inhibitors, Sarah Sagorsky, MPAS, PA-C, a physician assistant in the Upper Aerodigestive Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, remarked, “These days, regardless of tumor type, patients inevitably ask whether immunotherapy is an option for them. We reiterate what the oncologist has undoubtedly explained, namely that there is a better response rate with targeted therapies, but that they may eventually receive immunotherapy as the treatment plan evolves.”
Nuances of Patient Instructions
Crizotinib is administered as a capsule, taken twice a day, once in the morning and once in the evening. According to Ms. Sagorsky, “Ideally, we’d like to have patients take their [crizotinib] doses 12 hours apart. If that’s not possible, we explain that the doses should be spaced out as close to that as possible.” Pharmacists may help patients keep track of their dosing by providing two separate pill bottles, labeled “Morning dose” and “Evening dose.”
Notably, there may be some institutional variations in how patients are instructed to take oral crizotinib. At the Sidney Kimmel Comprehensive Cancer Center, “We usually start off by saying that the medication can be taken with or without food and that the capsules must be taken whole (ie, no opening, no crushing),” commented Ms. Sagorsky. Alternatively, Dr. Shaw, who practices at Massachusetts General Hospital in Boston, instructs patients to take the medication with food and that the evening dose should not be taken immediately before bed.
Ms. Sagorsky said a common question from patients is “What do I do if I miss a dose?” Patients are instructed to make up the missing dose if they realize it within about 6 hours of when they normally would have taken it. For times longer than that, she explained, patients are instructed to skip the missed dose and resume taking the medication with the next scheduled dose.
Establishing a Baseline
Most patients will have some sort of treatment-related toxicities, but until they actually take the medication, “we don’t know which ones,” observed Ms. Sagorsky. Moreover, it is important to perform appropriate baseline testing before initiating treatment with crizotinib.
“We do baseline testing—including laboratory tests, electrocardiograms (ECGs), and oxygenation—so that we have a way to evaluate the effect of the medication,” Ms. Sagorsky said. “In lung cancer patients, who may already have some degree of dyspnea, it may be difficult to determine whether shortness of breath is worse while on medication.” And, although rare, pneumonitis is possible. Likewise, because some bradycardia is expected, practitioners need to have the pretreatment data, including ECG, to make accurate assessments.
Preventing and Managing Adverse Effects
Serious and Fatal Adverse Events: Dyspnea (4.1%) and pulmonary embolism (2.9%) were the most frequent serious adverse events reported in patients taking crizotinib for metastatic ALK-positive NSCLC. Septic shock, acute respiratory failure, and diabetic ketoacidosis were the most frequent fatal adverse events and occurred in 2.3% of patients taking crizotinib.
Gastrointestinal Effects: “We advise patients to take crizotinib with food to mitigate any nausea, but if it becomes a problem, we will consider use of an antiemetic medication,” Dr. Shaw told JNCCN 360. Likewise, patients can develop either diarrhea or constipation, or both. Again, appropriate antidiarrheal medication or fiber/bulking agents can be discussed. “These issues may be particularly bothersome because the patient has to deal with them every day.” If the adverse effects are particularly acute, especially nausea, they may affect adherence. “I had a young patient who would skip his medication if he was going out because he knew it would trigger nausea. He ended up missing quite a few doses because of this effect,” Dr. Shaw said.
Reiterating Dr. Shaw’s comments about preventing and managing treatment-related nausea and/or vomiting, Ms. Sagorsky said, “the NCCN has classified crizotinib as a moderately to highly emetogenic drug (≥ 30% frequency of emesis),13 so if patients experience nausea and/or vomiting, we may prescribe an antiemetic. Sometimes just taking the medication with food will prevent these side effects, but if they persist, patients can take ondansetron with the crizotinib.” [Editor’s Note: the NCCN Guidelines13 also include granisetron and dolasetron as options.] Diarrhea (61%), nausea (56%), vomiting (46%), and constipation (43%) were reported by patients in the clinical trials of crizotinib.
With regard to other types of gastrointestinal issues, such as diarrhea or constipation, Ms. Sagorsky said, “we first want to determine that there isn’t any underlying infectious cause.” After more serious etiologies are ruled out, patients are advised to use over-the-counter remedies for diarrhea or constipation, as needed.
Visual Disturbances: The most common, although mild, adverse effect associated with crizotinib therapy is visual disturbance, which occurs a couple of days after starting treatment, Dr. Shaw explained. It is typically a change in the process of visually adapting from dark to light and has been described by patients as flashes in the visual field, visual trails, or persistence of images. These phenomena last for a few seconds up to a minute and then resolve. “We discuss the potential for these effects and warn patients about driving at night, when they may be affected by oncoming lights from another vehicle.” Ms. Sagorsky suggested that patients may want to wait a few days to determine how the medication affects them. If the visual field is significantly affected, “we will refer them to an ophthalmologist,” she said.
Liver Function: It is important to monitor liver function every 2 weeks after initiation of crizotinib, for the first 2 months, Dr. Shaw noted. Although usually asymptomatic, patients may experience elevation in alanine transaminase or aspartate transaminase levels, which can lead to liver damage or liver failure.
Bradycardia: Of note, most patients will experience a drop in heart rate by about 10 beats per minute (bpm) when they start crizotinib. “Generally, this is not much of an issue, but practitioners should be aware of this effect, especially in younger, athletic patients who may have a low baseline heart rate of about 50 bpm. If it drops to 40 bpm or even 30 bpm, patients may develop dizziness, lightheadedness, or even syncope,” Dr. Shaw pointed out. As long as patients are asymptomatic, the clinician can just monitor the ECG, she said. However, if symptoms appear, crizotinib should be held and then dose reduced.
Pneumonitis: Pneumonitis is a potential adverse effect of all targeted therapies in the setting of metastatic NSCLC, Dr. Shaw observed. It is fairly rare with crizotinib, with an incidence of about 2%, but it is important to recognize it early and to treat it. Crizotinib should be permanently discontinued in patients with pneumonitis.
Decreased Testosterone Levels: Although not included in the list of common adverse effects for crizotinib, “We’ve had a few men in whom crizotinib seems to have reduced testosterone levels,14” Ms. Sagorsky reported. “These patients might complain of fatigue or decreased libido/reduced sexual function. When their testosterone levels were noted to be low, we gave them replacement therapy.”
Edema: Dr. Shaw observed that if patients are doing well with crizotinib and stay on therapy for a period of time (eg, ≥ 2 months), they may develop edema, which is a cumulative effect. It usually affects the lower extremities, although it may also affect the hands and eyes. Simple measures such as elevating the legs and feet and using compression stockings may be sufficient for managing edema. But if the fluid retention is severe and refractory to conservative measures, diuretics or even dose reduction may be considered.
Notably, the duration of crizotinib treatment varies widely; some patients are on therapy for a few months, whereas others may continue for years, according to Dr. Shaw. “I have a patient who has been on crizotinib for more than 8 years and is doing well. Her only challenge, which is significant, is edema.”
Psychosocial and Emotional Distress
In addition to giving patients instructions and information, as well as a triage phone number for questions and reporting of adverse effects, it may be useful to refer patients to local lung cancer support groups and/or reputable advocacy websites (eg, LUNGgevity https://www.lungevity.org). Patients with ALK-positive NSCLC are often younger (ie, < 50 years of age) than the typical patient with lung cancer. A diagnosis of metastatic disease at that stage of life is unanticipated, usually shocking, and invariably causes psychosocial and emotional distress. “If the patient is amenable,” Ms. Sagorsky said, “we may help him or her connect with another younger patient so each has a ‘buddy’ with whom to share experiences and feelings.”
During the first few months of treatment, patients come to clinic every 2 weeks for monitoring and assessment. However, once it is determined that they are tolerating treatment well, visits may be scheduled farther apart. At that point, patients may begin to feel isolated from the cancer care team. “We do not proactively follow them (assuming that ‘no news is good news’),” Ms. Sagorsky explained, “but we let them know that we want to hear from them. We encourage them to call and check in. ‘You are not a bother. We want to know if you are not doing well.’” Sometimes patients might be reluctant to call or report a side effect because they are afraid that their dose may be reduced or that they may be taken off therapy. “We need to let them know that their quality of life is important and that there are many ways to manage their side effects or to adjust therapy to help them feel better,” she said.
The Decision to Switch Therapy
The decision to switch to a different therapy is often based on clinical impression, as well as scan results, Dr. Shaw explained. “We do an early scan at 6 weeks after treatment with crizotinib is started, to make sure it is having the effect we want. Later, if we see mild changes—minimal tumor growth, a few lung nodules—but the patient still feels very well, we will not automatically switch. If, on the other hand, the patient is symptomatic and the scans show significant disease progression, it may be time to consider next steps.”
Proliferation of ALK Inhibitors
Crizotinib is one of several first-line therapy options for patients with ALK-rearranged metastatic NSCLC,15,16 Dr. Shaw noted. Generally, crizotinib is a well-tolerated drug, but monitoring and management of adverse effects are important, she concluded. Newer next-generation ALK inhibitors include alectinib and ceritinib.15-18 Ceritinib is being assessed for patients with ROS1 rearrangements.19
Alice T. Shaw, MD, PhD, has received honoraria or consulting fees from Pfizer, Novartis, Genentech, Roche, Ariad, Daiichi-Sankyo, Taiho, EMD Serono, Foundation Medicine, Blueprint Medicines, and Loxo Oncology.
Sarah Sagorsky, MPAS, PA-C, has received honoraria from AstraZeneca, Boehringer Ingelheim, and Bristol-Myers Squibb.
- Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011;17:2081–2086.
- Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. N Engl J Med 2014;371:1963–1971.
- Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247–4253.
- Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 2010;17:889–897.
- Mazieres J, Zalcman G, Crino L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 2015;33:992–999.
- Pfizer Inc. Xalkoriâ (crizotinib). Full prescribing information. Available at http://labeling.pfizer.com/ShowLabeling.aspx?id=676&source=google&HBX_PK=s_crizotinib+pi&o=69985681%7C245244793%7C0&skwid=43700012995233262. Accessed May 3, 2017.
- Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 5.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 3, 2017.
- Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394.
- 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 2016;12:403–407.
- Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415–2426.
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–1833.
- ClinicalTrials.gov. Combination checkpoint inhibitor plus erlotinib or crizotinib for EGFR or ALK mutated stage IV non-small cell lung cancer. Available at https://clinicaltrials.gov/ct2/show/NCT01998126. Accessed May 4, 2017.
- Ettinger DS, Berger MJ, Aston J, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Antiemesis. Version 2.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 4, 2017.
- Weickhardt AJ, Doebele RC, Purcell WT, et al. Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer 2013;199:2383–2390.
- Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trial. Lancet 2017;390:29–39.
- Tan DS, Araújo A, Zhang J, et al. Comparative efficacy of ceritinib and crizotinib as initial ALK-targeted therapies in previously treated advanced NSCLC: An adjusted comparison with external controls. J Thorac Oncol 2016;11:1550–1557.
- Crinò L, Ahn MJ, De Marinis F, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: Results from ASCEND-2. J Clin Oncol 2016;34:2866–2873.
- Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. June 6, 2017 (early release online).
- Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 2017;35:2613–2618.