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New Antiangiogenics in NSCLC
New Antiangiogenic Options for Patients With Advanced NSCLC

Released: March 22, 2016

Expiration: March 21, 2017

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Case Report
 Mr. B is a 69-year-old white man who currently smokes 2 packs of cigarettes a week. He presented to his doctor with a 6-month history of persistent coughing, shortness of breath, and, within the last week, hemoptysis. A chest x-ray showed the presence of multiple lesions in both lungs so he was referred to an oncologist. After additional workup, he was diagnosed with stage IV NSCLC adenocarcinoma with brain metastases. Molecular testing revealed wild-type EGFR and ALK and a low level of PD-L1 expression (1% of cells). His ECOG performance status is 1, and he has comorbidities including long-term mild chronic obstructive pulmonary disease and hepatic dysfunction.

Mr. B was treated with cisplatin plus pemetrexed as initial therapy, followed by 4 cycles of maintenance pemetrexed, and achieved stable disease as his best response. However, within 6 months, his disease progressed with multiple metastases to the liver, spine, and ribs. Based on the currently available evidence, treatment with an immune checkpoint inhibitor is an option, but this may not be the best choice for Mr. B given the low level of PD-L1 detected in his biopsy specimen.

So, what other therapeutic alternatives do we have for this patient?

Ramucirumab
Until the last few years, the sole second-line options in this setting were erlotinib, pemetrexed, and docetaxel. Mr. B has wild-type EGFR, so erlotinib would not be the preferred second-line treatment option based on randomized trials that demonstrated improved outcomes with docetaxel compared with erlotinib for patients with wild-type EGFR tumors. Today, the addition of the FDA-approved and EMA-approved anti-VEGFR antibody ramucirumab to docetaxel may be an option for this patient, based on the results of the randomized phase III REVEL study of this combination as second-line therapy for stage IV NSCLC. In this robust study (N = 1253), median PFS was 4.5 months for the combination vs 3.0 months for docetaxel alone, and median OS was improved by 1.4 months. It appears that inhibiting angiogenesis with ramucirumab may be an acceptable choice both for patients with nonsquamous and squamous NSCLC and disease progression after platinum‑based chemotherapy, as in the case of Mr. B.

Nintedanib
In Europe, the EMA granted an approval for another antiangiogenic agent, nintedanib, a tyrosine kinase inhibitor that targets EGFR, PDGFR, FGFR, and VEGFR. This agent is approved as second‑line therapy for NSCLC with adenocarcinoma but not squamous cell carcinoma, based on results from the phase III LUME-Lung 1 study that showed a significant OS benefit for nintedanib and docetaxel vs docetaxel alone but only in the subset of patients with adenocarcinoma. In this group of patients, median OS was 12.6 months vs 10.3 months, a 2.3-month difference, whereas there was no significant OS difference in either the overall population or those patients with squamous cell histology. However, median PFS was significantly improved by nintedanib in the overall population, at 3.4 months for the combination vs 2.7 months for docetaxel and placebo (HR: 0.79). It should also be noted that a similar study comparing pemetrexed plus nindetanib vs pemetrexed plus placebo in nonsquamous NSCLC (LUME-Lung 2 trial) was stopped early due to futility at a prespecified interim analysis based on the investigator-assessed PFS only. A subsequent analysis of the available intent-to-treat population using independent review data showed a PFS benefit for patients treated with nintedanib plus pemetrexed compared with placebo plus pemetrexed (4.4 vs 3.6 months, respectively; HR: 0.83; P = .04) but no difference in OS between the 2 treatment arms.

So, in Europe, how would a clinician decide which of these 2 regimens including new antiangiogenic agents is best for an individual patient with adenocarcinoma, like Mr. B? The addition of ramucirumab to docetaxel was shown to improve the ORR, PFS, and OS in the overall population that included patients with nonsquamous and squamous histologies, whereas the addition of nintedanib to docetaxel was primarily of benefit to patients with adenocarcinoma. Although PFS with nintedanib was statistically significantly improved in the overall population, in my opinion, this was not a clinically meaningful benefit. One must also consider the balance between efficacy and toxicity when making a choice like this.

Understanding Toxicities
Both nintedanib and ramucirumab have a manageable increased risk of toxicity (vs docetaxel alone) but with no serious safety concerns and no effect on quality of life. With the combination of ramucirumab and docetaxel, most toxicities are related to docetaxel, with some additive hematologic toxicity due to ramucirumab. Of note, adding nintedanib to docetaxel significantly increased the rate of grade 2-4 diarrhea. In addition, some hypertension was seen with both of these agents in these large registration studies.

In the REVEL study of ramucirumab, no life-threatening severe hemorrhaging was seen, but bleeding events of any grade (eg, epistaxis) were more common with ramucirumab and docetaxel vs docetaxel alone. Of importance, in this study, no excess of respiratory tract bleeding events (eg, hemoptysis, pulmonary hemorrhage) was seen in patients with centrally located tumors, regardless of histology. This is significant because many bevacizumab treatment protocols exclude patients with centrally located tumors. A quality-of-life assessment using the Lung Cancer Symptom Scale showed no negative effect of ramucirumab.

What About Checkpoint Inhibitors?
Recently, immune checkpoint inhibitors that target PD-1 signaling have drawn a great deal of attention in oncology. However, for those patients with NSCLC who progress on first-line chemotherapy and who have very low or undetectable PD-L1 expression and adenocarcinoma histology, combination therapy with docetaxel plus either ramucirumab or nintedanib are reasonable alternatives. In studies of the anti–PD-1 antibody nivolumab, to date, no significant improvement in PFS or OS has been seen for patients with nonsquamous NSCLC and very low or undetectable levels of PD-L1 expression, and other classes of agents should be considered as therapeutic alternatives.

Conclusions
Angiogenesis is one of the key hallmarks of cancer and a key therapeutic target. First‑line options include bevacizumab in combination with carboplatin and paclitaxel, as in the ECOG 4599 study. The combination of cisplatin or carboplatin plus pemetrexed and bevacizumab is also widely used, at least in the United States. Both bevacizumab and nintedanib are approved by the EMA for the use in combination with docetaxel after first­‑line chemotherapy for NSCLC, but only in patients with adenocarcinoma histology. Ramucirumab is approved by the FDA and EMA in combination with docetaxel as second-line therapy for patients with NSCLC who progress on or after platinum-based chemotherapy. Overall, in my opinion, both ramucirumab and nintedanib (each combined with docetaxel) are reasonable options for patients with advanced NSCLC who are younger than 70 years of age and have a good performance status, although I generally lean toward the ramucirumab combination.

Have you used either of these new agents in your clinical practice? Let me know in the comments how they have benefited your patients.

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If Mr. B were your patient, what treatment would you recommend for him?
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