Paik Explains the Rationale for the Second-Line Standard for Patients With Squamous NSCLC

During a recent <em>Targeted Oncology </em>live case-based peer perspectives presentation, Paul K. Paik, MD, explained to a group of physicians the treatment considerations and decisions he makes when seeing a patient with non&ndash;small cell lung cancer.

Paul K. Paik, MD

During a recentTargeted Oncologylive case-based peer perspectives presentation, Paul K. Paik, MD, explained to a group of physicians the treatment considerations and decisions he makes when seeing a patient with non—small cell lung cancer (NSCLC). Paik, an associate attending physician and clinical director of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, reviewed treatment options when discussing the case studies of 2 patients with metastatic NSCLC.


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 former hypercholesterolemia and arthritis but had no known allergies. He was a former smoker but did not have a family history of lung cancer.

An MRI of the neck was completed which showed a spine lesion. A chest CT revealed a 4.3-cm right upper lung (RUL) mass with enlarged right hilar and right paratracheal lymph nodes. A PET scan showed18F-fludeoxyglucose 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 identified that the tumor was adenocarcinoma and was thyroid transcription factor (TTF)-1—positive. The patients was diagnosed with metastatic NSCLC, stage T2N2M1b.

Molecular testing by next-generation sequencing was negative forEGFR,ROS1,RET,BRAF,HER2, andNTRK.Immunohistochemistry was negative forALKgene rearrangements. The patient had PD-L1 expression in 0% of cells.

His laboratory values showed elevated carcinoembryonic antigen (CEA; 26 ng/ml) and a low albumin (3.4 g/dL), but he had a normal creatinine level, complete blood count (CBC), and liver function.

The patient was started on pemetrexed (Alimta) with carboplatin and pembrolizumab (Keytruda) every 3 weeks and vitamin B/folic acid supplement.

What are your initial impressions of this case?

A 62-year-old man presents with right-sided neck pain and some symptoms concerning for malignancy. He is a former smoker but has very little in terms of active concurrent medical problems. He has a series of imaging studies that show metastatic lung adenocarcinoma. He has a right-sided lung mass, avid mediastinal nodes, and also a metastasis in the thoracic and cervical spine. A brain MRI is negative. He has a biopsy which confirms lung adenocarcinoma that is TTF-1—positive.

The results of the molecular testing were all negative, but PD-L1 expression testing was also negative. Laboratory values showed relatively normal liver function.

Are you routinely testing for PD-L1 in patients with newly diagnosed NSCLC?

This is kind of an old question. I think almost everyone would say yes, although I am still finding some pathology reports where they have not sent it out and you still have to request it and it delays things. Hopefully, more pathology labs are starting to do this reflexively.

What first-line therapy options would you consider for this patient?

The patient was treated with the KEYNOTE-189 regimen [of pemetrexed and carboplatin], and they tacked on pembrolizumab.

CASE 1 (continued):

After 1 cycle of therapy with the triplet, the patient had an ECOG performance status of 1 and no physical exam he had no palpable lymph nodes, decreased breath sounds in the RUL, and persistent symptoms. His laboratory values showed that his CEA increased to 28 ng/ml, and his CBC showed mild anemia (hemoglobin [Hb], 11.0).

After cycle 2 on therapy, imaging showed progression in the right lung mass (5.2 cm) and several bone lesions. His labs showed increased CEA (34 ng/ml), decreased albumin (3.2), and decreased Hb (10.2).

What are your thoughts about this case after initial therapy?

After cycle 1, the patient is not feeling any better and on examination, there are decreased breath sounds. After 2 cycles of therapy, at 6 weeks, the patient has imaging which shows primary progression. The RUL mass is bigger and bone lesions are bigger and the patient is feeling less good because the Hb is down.

Could this possibly be pseudoprogression?

There is still talk about pseudoprogression, and retrospectively, the numbers have gone down the more we look at it. We used to think pseudoprogression was in 10% of patients, and it is down to 2% in some series now. I think the thought was that immunotherapy was the magic bullet and you just need to wait longer for it to work—but how long do you wait?

I think at the end of the day, the patient is not feeling clinically better; he is feeling clinically worse and it is not working. There is no point in dragging it out; he will just feel worse and be less set-up to get second-line therapy.

That is actually a concern: The portion of patients who end up getting second-line therapy in these trials is actually quite low. Despite the fact that the regimens work well, not a lot of patients are continuing on to second-line therapy and beyond.

What are the options for second-line therapy for this patient?

The standard now really is docetaxel with or without ramucirumab. Long gone are the days where we would continue using second-line immunotherapy, now that it has moved up to the first-line setting.

The docetaxel/ramucirumab indication approval is based on what are now older data—the REVEL study presented by Edward B. Garon, MD, back in 2014.1This was hot news then, and it was a very straightforward design—adding ramucirumab to docetaxel versus docetaxel in the second-line setting.

I had a keen interest in this because I treat the patients with squamous lung cancer at Memorial Sloan Kettering and, as you know, bevacizumab [Avastin] is not approved in this setting. It was really interesting to see what effect interfering with the VEGF/VEGFR axis would have on these patients, to see if there would be benefit. The somewhat exciting thing at the time was improvement in all of the efficacy metrics that were statistically significant. In the intention-to-treat population, there were modest benefits in terms of overall survival [OS] and progression-free survival, and the response rate was a lot better (23% vs 14%), all [statistically] significantly . On the forest plot, there was also a significant improvement in the patients with squamous cell lung cancer, which was nice—finally, an advancement in terms of second-line chemotherapy for those groups of patients.

Which patients saw the greatest improvement in OS in the REVEL trial?

REVEL was not designed or powered to look at subgroup analyses. One thing they did look at was whether or not, essentially, rapid progression on first-line therapy or primary progression had any role or influence in terms of the magnitude of benefit from docetaxel plus ramucirumab.2They looked at different cutoff points, [such as those who] progressed <4 weeks, <8 weeks, or <12 weeks after starting the first-line chemotherapy regimen. The key thing that they showed was that if you were a rapid progressor, if you progressed within 4 weeks of having started first-line therapy, then the magnitude of OS benefit seemed to be greater—here the hazard ratio is 0.40—than if you had progressed later on.

What is the impact of this analysis?

Again, it was not powered for this analysis. I do not really know why these cut points were chosen, but there is a thought that if you are a primary progressor, you may have a greater benefit to the docetaxel plus ramucirumab regimen. Data out there now have been presented and published. What people are doing with them, I do not know.

To some extent, it does not matter anymore, because we do not use second-line immunotherapy, which leaves us with docetaxel/ramucirumab. This is what we have, and everyone is going to get it. You either have someone who you think can tolerate the addition of ramucirumab to docetaxel or you do not. A fair number of patients are too ill for [us to be able] to say they will tolerate ramucirumab.

CASE 1 (continued):

The patient received docetaxel/ramucirumab (Cyramza).

What other data are coming out related to the treatment of progressive disease after a frontline immunotherapy regimen?

Another area of interest…is in the post first-line immunotherapy setting. Now everyone is getting immunotherapy. [Are these regimens] altering responsiveness to subsequent therapies, like docetaxel or docetaxel/ramucirumab? Those [studies] are ongoing, [and] some groups have reported that it actually seems to sensitize [patients] to chemotherapy; past immunotherapy seems to increase the response rates to subsequent chemotherapy in the second-line or third-line setting. These are all retrospective analyses, but this is a relevant question in the age of everyone getting immunotherapy. In the first-line setting, what does that do to the response to subsequent therapies? Additional groups are taking a look at that.


A 53-year-old woman presented with a lump in her left deltoid and no other signs or symptoms. Her medical history was insignificant, she was on no medications and had no smoking history.

An X-ray showed a 5-cm soft tissue mass and a lung biopsy identified squamous cell carcinoma, which was TTF-1—negative. Molecular testing was negative for known actionable mutations. A CT of the chest, abdomen, and pelvis showed intramuscular mass in the left deltoid, subcutaneous deposits in the back and thigh, a 5-cm right lower lobe spiculated mass, bilateral bulky mediastinal lymphadenopathy, and a 4-cm right adrenal mass. A brain MRI showed no evidence of central nervous system metastasis. He was diagnosed with stage T2aN3M1b NSCLC. Upon 22C3 antibody testing, revelated that the patient had a PD-L1 tumor proportion score of 0%.

The patient was started on carboplatin, paclitaxel, and pembrolizumab.

How often have you encountered this scenario of a patient with metastatic NSCLC with a squamous histology in a never-smoker?

Maybe about 4% to 5% of patients with squamous lung cancer are never-smokers. They are completely different genomically; we know this from plenty of sequencing data. In Asia, an association with human papillomavirus infection [has been shown], which we are not seeing so much in the United States. But the reason why this is important is because the National Comprehensive Cancer Network guidelines have a recommendation to consider molecular testing in this group of patients.3This is the only group of patients with squamous cell lung cancer for whom we routinely recommend molecular testing, because there is a subset where the diagnosis is either wrong, or else there is a phenomenon called solid adenocarcinoma, which looks like squamous cell lung cancer histologically but not molecularly.

What molecular testing should be ordered?

Data show that you should just do the routine testing that you normally do, and some small case series show that the targeted therapies can be effective in these patients also.

What options would you consider for frontline therapy for this patient?

In this PD-L1—negative patient, I think the choices are obvious based on the data: either chemotherapy or chemotherapy plus pembrolizumab at this point.

CASE 2 (continued):

Imaging at 6 months showed widespread progression with new and enlarging lesions, including a significant increase in her soft tissue and lymph node disease, collapse of her right lower lobe, and new liver lesions.

How would you characterize her response to chemotherapy and immunotherapy?

The patient was started on the KEYNOTE-407 (NCT02775435) regimen of carboplatin, paclitaxel, and pembrolizumab. The case does not mention whether the patient had a response or what the clinical benefit was, perhaps on purpose. But at 6 months of the regimen, there is progression of disease with both enlarging as well as new disease.

Is 6 months&rsquo; duration of clinical benefit a good, bad, or intermediate response?

It is not the best response in the world, but it is better than primary progression and somewhat in the gray area.

What options would you consider for second-line therapy for this patient, and why?

The [choice would be for] docetaxel with ramucirumab. This relates to adenocarcinomas and squamous cell lung cancers treated with chemotherapy/immunotherapy in the first-line setting. They are getting 4 cycles of platinum-doublet chemotherapy at the beginning of their treatment, and that is it; most everyone else is getting just pembrolizumab. The question arises: If there is progression on maintenance pembrolizumab, and it has been 12 months or 18 months and then they progress, would you rechallenge with platinum-doublet chemotherapy? I think that is among the underlying questions here, and this is something that I consider for patients who are feeling relatively well. With the limited amount of chemotherapy that they get—which is 4 cycles, particularly if they are responding to the therapy—what they are responding to is somewhat arbitrary. It could be that they have responded to the chemotherapy component, but you just do not know. It raises the potential of rechallenging them with platinum-doublet chemotherapy after that.


  1. Garon EB, Ciuleanu TE, 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 3 trial.Lancet.2014;384(9944):665-673. doi: 10.1016/S0140-6736(14)60845-X.
  2. 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.
  3. NCCN Clinical Practice Guidelines in Oncology. Non—Small Cell Lung Cancer, version 3.2019. Published January 18, 2019. Accessed March 18, 2019.