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Fidler Examines a Case of NSCLC With Rapid Progression on Standard Frontline Therapy

Lisa Astor
Published Online:9:07 PM, Tue June 25, 2019
Mary Jo J. Fidler, MD
Mary Jo J. Fidler, MD
During a recent Targeted Oncology live case-based peer perspectives presentation, Mary Jo J. Fidler, MD, discussed with a group of physicians the diagnostic workup and the considerations for treatment when she sees a patient with non–small cell lung cancer (NSCLC) in the clinic. Fidler, an associate professor of medicine at Rush University Medical Center in Chicago, reviewed treatment options in the first and second line based on a case study of a patient with NSCLC who experiences rapid progression on her first-line regimen. 

Case
A 62-year-old man presented to his primary care physician complaining of persistent right-sided neck pain; 2 months later, he developed decreased appetite, lethargy, and a dry cough. He had a medical history of hypercholesterolemia and arthritis, but he had no allergies. He was a former smoker with a 20 pack-year history. 
An MRI of the neck revealed a cervical spine lesion, and a chest CT showed a 4.3-cm right upper lung (RUL) mass with enlarged right hilar and right paratracheal lymph nodes. A PET scan showed fluorodeoxyglucose uptake in the RUL mass, the hilar and paratracheal nodes, and multiple cervical and thoracic vertebrae. A brain MRI was negative for metastases. CT-guided biopsy of the RUL mass showed that the mass was adenocarcinoma and was thyroid transcription factor 1–positive. He was diagnosed with metastatic NSCLC, stage T2N2M1b.
Next-generation sequencing (NGS) was performed on the tumor tissue, which was negative for EGFRROS1RETBRAFHER2, and NTRK. Immunohistochemistry (IHC) was also negative for any ALKgene rearrangements. He had PD-L1 expression in 0% of cells.
Laboratory values were notable for elevated carcinoembryonic antigen (CEA) levels of 26 ng/mL and a low albumin of 3.4 g/dL. He had a normal complete blood count (CBC), creatinine clearance, and liver function.

Targeted Oncology: Why was ALK testing performed using IHC as opposed to NGS for this patient?
Fidler: They are talking about doing a validation to use [immu­nohistochemistry to test for ALKrearrangements] because you are testing for the protein. The test that first came out was the FISH [fluorescence in situ hybridization] break-apart probe. Then inter­estingly, we were told that the Chicago area sees more ALKmuta­tions than in some other areas, but a lot of us were using NGS, which is sequencing the entire gene. It is possible that NGS may capture a bit more, but IHC has not been validated as the way [to test for this]. Some institutions are actually using IHC as a screen, so if they have no ALK protein by IHC, then checking for the fusion or sequencing the ALK gene [may not be necessary]. This patient had IHC that was negative for ALK, so probably not a player.

What first-line therapy option would you recommend for this patient, and why? 
The patient has PD-L1 expression of 0%, so he would fall into the tumor proportion score of <1% [portion of the KEYNOTE-189 trial]. There is still a benefit to adding the pembrolizumab [Keytruda] to chemotherapy, even if there is no PD-L1 expression.1

Based on the case description, what are your impressions of the patient at this point? Does this patient present with progressive disease? 
The patient was started on the triplet combination per recom­mendations and, after cycle 2, had progression in the right lung and several bone lesions. This patient had a tumor marker that was followed, and the marker went up. Overall, he had progres­sion of disease after 2 cycles.

Case (continued):
The patient was started on pemetrexed (Alimta) and carboplatin with pembrolizumab every 3 weeks along with vitamin B/folic acid supplement.
After 1 cycle of treatment he had an ECOG performance status of 1, no palpable lymph nodes, decreased breath sounds in the RUL, and persistent symptoms in a physical exam. 
His labs were notable for an increased CEA level of 28 ng/mL and his CBC showed mild anemia with a hemoglobin (Hb) of 11 g/dL.
After the second cycle, imaging showed progression in the RUL mass (5.2 cm) and several bone lesions. His labs were notable for increased CEA (34 ng/mL), decreased albumin (3.2 g/dL), and decreased Hb (10.2 g/dL).

Do you think there is a possibility that this could be pseudoprogression? What is the estimated frequency of pseudoprogression? 
My mentor had a patient who developed a massive pleural effu­sion on therapy [and] had to get an emergency drainage and subsequent imaging with a dramatic response, and [the patient] has been in remission for 3 years. I think it is rare, but it is a real thing. [The frequency is probably] less than 5%. 

I have had patients who developed new nodules in their lungs that looked inflammatory and then they went away. I have had some patients for whom the CT in general looked much worse, but their pain is gone, and they are doing great. But it is not that common. 

I do not follow tumor markers in my patients. I suppose it could correlate with progression if you are worried about pseu­doprogression. I think that most of the time, unfortunately, it is legitimate progression. 

What treatment option would you recommend for this patient next? 
There’s always docetaxel. Afatinib [Gilotrif] is approved for patients with squamous disease in this setting but not for patients [with nonsquamous disease]—they lost this indication. I think docetaxel is still a reasonable option. We often use docetaxel plus ramucirumab [Cyramza] in our group. 

What are the data that support this treatment regimen in the second-line setting? 
The randomized REVEL study [looked at] docetaxel, the standard every-3-week dose, with or without ramucirumab, which is also dosed every 3 weeks.2Ramucirumab is an anti-VEGF agent. It is targeting the receptors, and VEGFR2 is the one that does the main signaling through the VEGF pathway. 

This was a study combining the VEGFR2-targeted monoclonal antibody with docetaxel. Admittedly, it is not the nice separa­tion [of curves] we saw with our frontline immunotherapy trials. But one thing that sold us on the combination is if you look at overall survival [OS], you have a statistically significant bene­fit; progression-free survival [PFS], also a benefit; and response rate, too, was a little bit higher, with a pretty significant hazard ratio compared with placebo and docetaxel. Everything trends toward the fact that this drug is probably additive to docetaxel. 

Do certain patients derive the most benefit from this combination? 
This trial was not powered for different subgroup analyses, but one of the things the company looked at [was that there are] some patients who may derive even more benefit from the addi­tion of the antiangiogenic agent. This is to look at the concept of a rapid progression. 

[Regarding] patients based on their duration of first-line ther­apy, investigators separated patients into groups with less than 4 weeks, less than 8 weeks, and less than 12 weeks of initial therapy. This study was exploratory, and the trial was not intended to look at this question. But you have a hazard ratio of 0.40 [for OS] in the group who had progressed quickly. If a patient has blown right through their immunotherapy, they can receive the doublet; and I do use a lot of docetaxel plus ramuci­rumab for them.3

The trial had treatment until progression; some other trials looked at 6 cycles of docetaxel in the past. I typically keep them on both until progression, but I dial down the docetaxel because there is some neuropathy. We have taken people off the docetaxel and kept them on the ramucirumab, and it could be that these drugs are a little more synergistic when they are together. 

There are no data that I’ve seen for continuing ramucirumab alone, and, anecdotally, for the patients we pulled off the chemo­therapy and left on ramucirumab, we’ve kind of felt that they progress a little faster than if we’ve added back the chemother­apy. I think there is some synergy with the combination. 
The subgroup with the rapid progression is quite intriguing. The hazard ratio is 0.40 for the OS and 0.44 for the PFS. We have an overall survival of 8.8 versus 3.2 months. 

What is the toxicity profile with this combination? 
It is like a VEGF agent with the typical wound-healing issues with antiangiogenic agents. Docetaxel is not the easiest, and I feel as if [ramucirumab] is not adding a whole lot of toxicities. You still have to do the proteinuria monitoring and the blood pres­sure monitoring. There is an increased risk of clots and arterial bleeds in theory.
 
 
References:
  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. 
  2. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 2 trial. Lancet. 2014;384(9944):665-673. doi: 10.1016/S0140-6736(14)60845-X. 
  • Reck M, Paz-Ares L, Bidoli P, et al. Outcomes in patients with aggressive or refrac­tory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181-187. doi: 10.1016/j.lungcan.2017.07.038.


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