Ann Tsao, MD: The REVEL trial, which looked at docetaxel versus docetaxel/ramucirumab, demonstrated that the ramucirumab arm increased progression-free and overall survival by roughly 1.4 or 1.5 months. We do know that for all patients, all comers, this did have benefit. But in the subgroup analysis, when they divided it up by looking to see which patients had rapid progression, as opposed to those who did not, after frontline therapy, they demonstrated that the rapid progressors had just as much of a survival benefit as those who had not progressed rapidly. I believe that the subgroup analysis did their cutoffs at 9 weeks and at 12 weeks. It is very interesting that patients who progressed rapidly gained a significant survival benefit compared with the other patients in the trial.
Ronald J. Scheff, MD: One of the most problematic aspects in non—small cell cancer treatment are the patients who have chemotherapy-refractory disease; patients whose disease does not respond to frontline chemotherapy. When we look at the REVEL trial, we can pull out those patients who, in the first-line setting on platinum doublet chemotherapy, had refractory disease. These are high-risk patients who did not respond to chemotherapy. They are at risk of continued disease progress; they will be at risk of dying very early.
When looking back at the REVEL trial, what’s interesting and important to note is that even patients who, in the frontline setting—before they were randomized to docetaxel versus docetaxel-ramucirumab—had chemorefractory disease still saw a benefit in progression-free survival and a trend toward benefit in overall survival when they were treated with ramucirumab in addition to docetaxel. So, it’s a very important subgroup of patients, patients who are at high risk of disease progression and death because they did not have any benefit from frontline chemotherapy. Those patients did see benefit when ramucirumab was added to docetaxel in the second line. I think that when considering choices of second-line therapy for these chemorefractory patients, it’s important to remember these data. Ramucirumab adds benefit to docetaxel in this specific patient group and should be considered as a second-line treatment option.
Benjamin P. Levy, MD: The sequencing strategies for non—small cell lung cancer are rapidly evolving, and we have new data from the REVEL trial regarding patients who are rapidly progressing. These are patients whose tumors are progressing after 4 cycles of a platinum doublet and who are not getting maintenance, or even after 2 cycles. These patients are in trouble, are generally not doing well, and need good effective therapies. What we’ve learned from the REVEL trial is that in patients who are rapidly progressing, the addition of ramucirumab to docetaxel offered a meaningful improvement in PFS and response rates and overall survival, most importantly. We don’t normally see overall survival advantages in this patient population that is rapidly progressing, so to show that in a subset analysis is important.
This is also important in terms of how I sequence therapies. If a patient is rapidly progressing on a platinum doublet and their PD-L1 may be low, this is a patient for whom I maybe wouldn’t consider immunotherapy. Maybe this is a chance to offer them docetaxel and ramucirumab because we may only have 1 chance to get it right. Not to say that I-Os don’t play a role for patients in this setting, but I would say that if a patient is on a platinum doublet up front and their tumor is growing rapidly through that platinum doublet, we need to think critically about when to use I-O, when to use immunotherapy, and when to use docetaxel and ramucirumab. For that patient who’s rapidly progressing, if I do use second-line docetaxel and ramucirumab, then in the third line I would maybe consider immunotherapy if I didn’t use immunotherapy in the induction regimen with a platinum doublet.
Ronald J. Scheff, MD: Patients who have chemotherapy-refractory disease in the first-line setting are at high risk of disease progression and death. We’re always looking for better ways to treat these patients. The REVEL trial included patients who were chemorefractory in the grouping for second-line treatment, and even in that group of patients, the addition of ramucirumab to docetaxel yielded benefit. So, ramucirumab in this instance is meeting an important need for these patients who have chemorefractory disease.
I also think it’s important to bear in mind some of the immunotherapy trials, specifically the CheckMate-057 trial, which was in the second-line setting comparing nivolumab versus docetaxel. In the first 3 months of that trial, there was actually an excess of deaths in the nivolumab arm compared with the docetaxel arm. When the characteristics of those patients who did less well with nivolumab during the first 3 months have been looked at, one of the striking characteristics was chemotherapy-refractory disease, disease that did not respond to frontline chemotherapy before patients were put on nivolumab versus docetaxel. Another factor that was important was having a very low or 0% PD-L1 score. In that instance, with these patients who are chemorefractory, it may be that ramucirumab and docetaxel is an option that is more supported by data than immunotherapy.
Transcript Edited for Clarity