Case 3: Rapidly Progressing Stage IV NSCLC Following I-O

Anne S. Tsao, MD:Case 3 is the case that all of us are afraid of. This is the rapidly progressing metastatic stage IV lung cancer patient following immuno-chemotherapy. This is a 66-year-old lady who’s a current smoker. She was diagnosed with high-grade lung adenocarcinoma 7 months ago. A CT [computed tomography] scan of the chest shows 3 lobular lesions in the left lower lobe of the lung, measuring about 4.5 cm, 2.1 cm, and 3.3 cm. At the time of her presentation, she had widely disseminated brain metastases. She did get whole-brain radiation. While that was done, she had microprofiling of her tumor. Unfortunately, it didn’t show any actionable driver mutations. But, you did get a little, additional note saying that the tumor cellularity was poor. And, they didn’t do the FISH [fluorescence in situ hybridization] analysis. So this is, again, one of those things that makes all medical oncologists fringe.

The PD-L1 [programmed-cell death ligand 1] was also run, or supposedly run. Unfortunately, it comes back indeterminant. So, you don’t even have that piece of information. She ends up getting carboplatin/pemetrexed/pembrolizumab, and her CT scan at 12 weeks shows massive progression in all 3 lung lesions that were being followed. She already had whole-brain radiation therapy, so her brain disease was stable. But, she now has new liver and bone metastases. She’s got worsening fatigue and her performance status, which used to be 0, is now 1. I want you guys to keep that in mind while we review some of the data.

This is a subset analysis from the REVEL trial. The REVEL trial, just as a brief recap, was a phase III study of docetaxel with and without ramucirumab for second-line non—small cell lung cancer. The study originally came out before the era of immunotherapy’s hit. Very quickly, I’ll recap the study design.

This was for all stage IV non—small cell lung cancer patients—both nonsquamous and squamous cell carcinoma. Everyone had to have had at least 1 platinum-based chemotherapy with or without maintenance therapy. They could have had prior bevacizumab. The performance status had to be 0 or 1. They were stratified by performance status, gender, and prior maintenance therapy. Since this was an international study, they also stratified by location, geographically. The primary endpoint was overall survival. When they gave treatment, ramucirumab was given at 10 mg/kg. In both arms, docetaxel was given at 75 mg/m².

Patients continued on treatment until progression or unacceptable toxicity. Again, there was a significant overall survival benefit. Ramucirumab, added to docetaxel, demonstrated a median overall survival of 10.5 months. The docetaxel lower arm was 9.1 months. This translated into a hazard ratio of 0.86, with aPvalue that was statistically significant—.023.

Again, the trial was not powered to do this exploratory analysis. It really looked at whether or not patients who rapidly progress gain benefit from ramucirumab plus docetaxel. They took different cutoffs for how quickly they progressed on first-line therapy, and then analyzed each of these subgroups by survival outcome, depending on which arm they were on in the REVEL trial.

In the patients who received docetaxel/ramucirumab, the bottom line was that all of these patients derived significant benefit. It appeared to be an increase of about 1.5 months for progression-free survival, and about 2 months for overall survival. It did appear that the ramucirumab and docetaxel arm gained some benefit in those rapid progressors from frontline therapy.

If you look at the Kaplan-Meier curves for overall survival and lump together all of these refractory rapid progressors, the median overall survival for the patients who got ramucirumab/docetaxel was 8.3 months. In those who got docetaxel, alone, it was only 6.3 months. This translated into a hazard ratio of 0.86. Again, this was an exploratory analysis. ThePvalue didn’t reach statistical significance.

But interestingly, the median progression-free survival in refractory patients, when you looked at the patients who got docetaxel/ramucirumab, was 4 months compared to docetaxel, alone—2.5 months. The hazard ratio was 0.71, and thePvalue did reach statistical significance. So, there did appear to be significant benefits seen in this refractory population of patients with docetaxel/ramucirumab. When they did the initial analysis, in terms of quality of life when looking at symptoms, it actually appeared that ramucirumab seemed to improve side effects for these patients—toxicities from their malignancy, not from treatment. It especially appeared to benefit patients who had fatigue or dysthymia. Again, this was an exploratory analysis, but it is food for thought that this regimen may significantly improve our patients.

Transcript edited for clarity.