Ronald J. Scheff, MD

Ramucirumab for Metastatic Non-Small Cell Lung Cancer

Ronald J. Scheff, MD

According to the National Cancer Institute (NCI), lung cancer is the most common cancer among men and women in the United States. The NCI estimates that the number of new cases of lung cancer in 2019 will be around 225,000. In addition, lung cancer is the leading cause of cancer death in the United States; with nearly a quarter of all cancer deaths this year expected to be caused by lung cancer.¹

For decades, chemotherapy alone was the sole systemic therapeutic option to treat lung cancer.  Since the turn of the century, however, advances in molecular biology and clinical immunology have led to the development of new types of systemic treatments that target newly discovered cellular pathways and genetic pathways involved in tumorigenesis.²

Among these new biological agents is ramucirumab — a recombinant human IgG1 monoclonal antibody that targets vascular endothelial growth factor receptor 2 (VEGF-R2). Ramucirumab was approved by the US Food and Drug Administration 5 years ago, in combination with docetaxel chemotherapy, to treat metastatic NSCLC (mNSCLC) that has progressed following platinum-based therapy.^3,4

As a VEGF-R2 antagonist, ramucirumab inhibits specific VEGFR ligands that contribute to the proliferation and migration of endothelial cells.⁴ Through this mechanism, ramucirumab works to inhibit angiogenesis and the development of oncogenic cells.⁵

Guidelines-Based Treatment for mNSCLC

The latest National Comprehensive Cancer Network (NCCN) guidelines include ramucirumab plus docetaxel as a recommended second-line or later systemic therapy treatment option for patients with mNSCLC who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 following disease progression on or after prior systemic therapy with checkpoint (PD-1/PD-L1) inhibitors and platinum-based chemotherapy.⁶

Ramucirumab plus docetaxel may be used following initial platinum-based cytotoxic therapy in patients who are intolerant of immunotherapy.⁶

Dosing

Ramucirumab is dosed at 10 mg/kg via IV infusion over 60 minutes on day 1 of a 21-day cycle, administered before docetaxel infusion at 75 mg/m², and is typically continued until disease progression or intolerance.^4. Premedication with steroid and/or diphenhydramine is recommended.

Pathologic and Genetic Testing

NCCN guidelines emphasize the need to determine up front the histologic subtype of mNSCLC and, when indicated, to test for targetable genetic alterations such as EGFR and BRAF mutations and ALK and ROS1 gene rearrangements. Using specific medications to target these specific alterations, according to the NCCN, “has been shown to decrease tumor burden, decrease symptoms, and dramatically improve the quality of life for patients with specific genetic alterations.”⁶

It is recommended that patients whose cancers harbor targetable genomic mutations such as EGFR and ALK receive approved targeted therapies for those molecular aberrations before receiving other agents such as ramucirumab.^4,6

REVEL Study: Efficacy

The FDA approval of ramucirumab for NSCLC was granted based on the outcomes of the phase 3 REVEL trial, which was published in 2014. Given the number of changes in the treatment of non-small cell lung cancer 2014 may seem like a long time ago, but in fact I still find the regimen of ramucirumab extremely relevant to my practice today. In this international, randomized, double-blind clinical trial, ramucirumab plus docetaxel (628 patients) was compared to docetaxel plus placebo (625 patients) in patients with disease progression on or after platinum-based chemotherapy. All of the 1253 patients included in the trial had stage 4, locally advanced or metastatic disease and an ECOG PS of 0 to 1. Median age was 62 years (range: 21-86), 33% were female, and 18% were people of color. About three quarters of participants in both trial arms had nonsquamous histology while the remainder had squamous histology.⁴

The primary endpoint was overall survival (OS). Ramucirumab plus docetaxel demonstrated significant improvements in OS compared with docetaxel plus placebo: 10.5 months (95% confidence interval [CI], 9.5-11.2) versus 9.1 months (95% CI, 8.4-10.0), respectively, with a hazard ratio of 0.86 (95% CI, 0.75-0.98; P =.024).⁴

In addition, ramucirumab plus docetaxel significantly improved the secondary endpoints compared with docetaxel plus placebo: overall response rate (P <.001) and progression-free survival (P <.001).⁴

REVEL Study: Adverse Effects

In the same study, investigators reported that febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%) were the most common serious adverse events (AEs) in the patients treated with ramucirumab plus docetaxel. Among all grades of common AEs, neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation were the ones reported greater than or equal to 30% of the time in the ramucirumab plus docetaxel group that also occurred greater than or equal to 2% more often than in patients who received placebo plus docetaxel.⁴

The most common serious AEs reported in the REVEL trial are ones typically associated with docetaxel rather than ramucirumab. A strategy used in my practice to minimize toxicity from the combination of ramucirumab and docetaxel is to attenuate the starting dose of docetaxel. While most patients in the REVEL trial received a starting dose of docetaxel 75 mg/m² with ramucirumab, some patients in the trial started with docetaxel dosed at 60 mg/m² because of concerns regarding toxicity. We have found in my practice that a starting dose of docetaxel 60 mg/m² IV (while keeping the ramucirumab dose at 10 mg/kg IV) significantly minimizes the chance of febrile neutropenia and stomatitis, without compromising efficacy. For patients with ECOG PS 2 we sometimes start the docetaxel even lower (eg, 50 mg/m²), while keeping the ramucirumab dose 10 mg/kg. The patients with mNSCLC we are treating with ramucirumab and docetaxel have received cytotoxic chemotherapy previously, and in some cases for a long time as maintenance therapy. Their bone marrow reserve may be compromised. Reducing the dose of docetaxel is a way to minimize the risk of marrow and related toxicities.

We also find in practice that patients may become intolerant of docetaxel altogether after 4 to 6 cycles of therapy.  For such patients we discontinue docetaxel and continue ramucirumab therapy as a single agent, as was done in the REVEL trial.  We have seen prolonged responses using this strategy.

Additional Considerations

REVEL and other studies (1,916 patients), conducted in participants with various forms of cancer, revealed important considerations and precautions regarding treatment with ramucirumab.⁴ These considerations are summarized below.

• Hemorrhage: An increased risk of hemorrhage is associated with ramucirumab. Incidence of all Grade hemorrhage was 13% to 44%; grade 3 or higher hemorrhage was 2% to 5%. Ramucirumab should be discontinued in any patient with grade 3 to 4 bleeding. Physicians should advise patients to contact the office if they experience bleeding or lightheadedness.
• Gastrointestinal (GI) perforations: Increased risk of GI perforations has been found with ramucirumab. Incidence of all grade and grade 3 or higher hemorrhage was less than 1% to 2%. Physicians should advise patients to contact the office if they experience severe diarrhea, abdominal pain, or vomiting.
• Impaired wound healing: Agents that inhibit the VEGF or VEGFR pathways are known to impair wound healing. Ramucirumab should not be administered for 4 weeks before elective surgery, or for 4 weeks after major surgery and until the wound is completely healed. Ramucirumab should be discontinued in any patient with impaired wound healing.
• Arterial thromboembolic events (ATEs): Incidence of all grades were 2% to 3%; Grade 3 or higher ATEs were 1% to 2%. Ramucirumab should be discontinued in any patient who experiences an ATE.
• Hypertension: Because of an increased incidence of severe hypertension among patients receiving ramucirumab (all Grade hypertension 11% to 26%; Grade ≥3 6% to 15%), physicians must ensure that hypertension is controlled before beginning therapy. In addition, clinicians should advise patients to monitor their blood pressure at least every two weeks during therapy and encourage them to contact the office if blood pressure increases or if they experience severe headaches, lightheadedness, or neurologic symptoms.
• Hepatic impairment: Dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with Child-Pugh B or C cirrhosis, clinical deterioration was reported.

In addition to these events, women of child-bearing age should be educated about using ramucirumab. While no studies have been conducted in pregnant animals or humans, what’s known about the agent’s mechanism of action (inhibition of angiogenesis) suggests that it could affect female reproduction and fetal development. Contraception is recommended during treatment and for 3 months after the last dose.⁴

Likewise in women who are lactating, while no animal or human studies have been conducted, the prescribing information for ramucirumab recommends against nursing during treatment and for 2 months after the last dose.⁴

In our practice we explain to patients that severe AEs from ramucirumab are uncommon (less than 5% incidence) but can be life-threatening. We include in our discussion the risk of pulmonary hemorrhage. As in the REVEL trial, we do not prescribe ramucirumab to patients with history of recent hemoptysis, cavitary lung lesion larger than 1 cm in diameter, or with a tumor appearing on CT scan to involve a major blood vessel.  Similarly, also because of the risk of bleeding, we do not prescribe ramucirumab to patients with untreated brain metastases or history of colitis.

At the same time, we have found it important to inform and reassure patients that mild epistaxis (particularly in the morning) is common on ramucirumab therapy, and is typically self-limited.

Latest Data on Ramucirumab

Three studies published since the beginning of 2019 offer new insights into the treatment of NSCLC with ramucirumab, specifically in regard to sequencing with immune checkpoint inhibitors (ICIs).^7-9

One study conducted by Molife et al showed that overall survival was most prolonged in the group who received sequential ramucirumab- and ICI-based therapy.⁷ Another analysis, authored by Shiono and colleagues, demonstrated a higher overall response rate in patients who received ramucirumab + docetaxel immediately after failure with the ICI nivolumab compared with regimens without prior nivolumab.⁸ In a third study, Tamura et al found similar results as Shiono in patients with advanced NSCLC.⁹

Discussing Therapy With Patients

Per guideline recommendations and per our own experience in practice, patients receiving ramucirumab are patients who have received systemic therapy for mNSCLC before. In most cases these patients have received cytotoxic chemotherapy, immunotherapy with checkpoint inhibitors, and possibly therapy with agents that target actionable mutations such as EGFR and ALK. In these “experienced” patients, it is important to again review the range of possible treatment outcomes, ranging from complete response to absence of response, and to review potential side effects, particularly those that are unlike others they may previously have experienced.  These would include abnormal bleeding, thrombosis, impaired wound healing, and hypertension. Patients should be instructed to immediately report any abnormal bleeding, change in respiratory status, lower extremity pain or swelling, or new neurologic symptoms.

Conclusion

With efficacy superior to docetaxel alone (REVEL trial), the palliative systemic therapy regimen of ramucirumab plus docetaxel remains a relevant treatment option in the management of advanced non-small cell lung cancer.  Indicated for disease that has progressed on platinum based chemotherapy, ramucirumab and docetaxel has become my go-to regimen for platinum-resistant patients who are not at excess risk of serious pulmonary or CNS hemorrhage.  With manageable toxicities, I have also found ramucirumab and docetaxel to be a very versatile regimen; it is indicated across all histologies of non-small cell lung cancer (including squamous cell), and may be efficacious even in patients previously treated with other taxanes, other anti-VEGF pathway agents, immunotherapy, and targeted therapies.

References

1. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Lung and Bronchus Cancer. Available at: https://seer.cancer.gov/statfacts/html/lungb.html. Accessed: June 3, 2019.
2. Forde PM, Ettinger DS. Targeted therapy for non-small-cell lung cancer: past, present and future. Expert Rev Anticancer Ther. 2013;13:745-758.
3. Larkins E, Scepura B, Blumenthal GM, et al. U.S. Food and Drug Administration approval summary: ramucirumab for the treatment of metastatic non-small cell lung cancer following disease progression on or after platinum-based chemotherapy. Oncologist. 2015;20:1320-1325.
4. CYRAMZA Prescribing Information. Eli Lilly and Company. Indianapolis, IN.
5. Cobo M, Gutiérrez V, Villatoro R, et al. Spotlight on ramucirumab in the treatment of nonsmall cell lung cancer: design, development, and clinical activity. Lung Cancer (Auckl). 2017;8:57-66.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 5.2019 — June 7, 2019.
7. Molife C, Hess LM, Cui ZL, et al. Sequential therapy with ramucirumab and/or checkpoint inhibitors for non-small-cell lung cancer in routine practice.Future Oncol. doi:10.2217/fon-2018-0876
8. Shiono A, Kaira K, Mouri A, et al. Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non-small cell lung cancer patients. Thorac Cancer. 2019;10:775-781.
9. Tamura N, Horinouchi H, Sekine K, et al. Efficacy of subsequent docetaxel +/− ramucirumab and S-1 after nivolumab for patients with advanced non-small cell lung cancer. Thorac Cancer. 2019;10:1141-1148.