Langer Reviews a Case Study of a Patient With Stage III NSCLC

Corey J. Langer, MD

Corey J. Langer, MD

During a recentTargeted Oncologylive case-based peer perspectives presentation, Corey J. Langer, MD, discussed with a group of physicians the diagnostic workup and the considerations for treatment he makes when seeing a patient with non—small cell lung cancer (NSCLC) in the clinic. Langer, director of thoracic oncology, Abramson Cancer Center, and professor of medicine, Hematology/Oncology Division, University of Pennsylvania, reviewed treatment options based on a case study of a patient with stage III NSCLC.

Case

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion. His medical history was notable for hyperlipidemia, which was well managed on simvastatin; hypothyroidism, which was managed on levothyroxine; and chronic obstructive pulmonary disease, which was managed on inhalers. He had recently quit smoking but had a 40-pack-year history.

On physical exam noted intermittent wheezing and he had an ECOG performance status of 1. His creatinine clearance was within normal limits.

A chest CT revealed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes measuring 2.5 cm and 1.7 cm. Moderate emphysema was also noted. A PET scan confirmed a lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. A brain MRI was negative.

In a pulmonary function test (PFT), his forced expiratory volume in 1 second was 1.2 L and his diffuse capacity of lung for carbon monoxide was 35%. A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma at primary site with positive nodes in stations 4R and 7; level 4L was negative. He was diagnosed with NSCLC T2aN2M0, stage IIIA.

Based on the bulk and extent of mediastinal disease and active emphysema, the patient’s cancer was deemed unresectable, and he was referred for consideration of concurrent chemotherapy and radiation.

Targeted Oncology:What are your impressions of this patient?

Langer:This is a pretty typical patient with typical comor­bidities. He is a reasonably healthy guy. [He was] staged in the AJCC7 [American Joint Committee on Cancer Staging Manual, Seventh Edition] and also in the TNM [criteria]. Based on the bulk and the extent of mediastinal disease, the active emphysema, and those questionable PFTs, the tumor was deemed unresectable. Though, if this had been a healthy patient, you could conceive, particularly after the 2019 ASCO [American Society of Clinical Oncology] Annual Meeting, some new adjuvant approach with chemotherapy or chemotherapy/radiation followed by surgery. He is referred by consideration for concurrent chemotherapy and radiation.

Targeted Oncology:Do you typically order genetic testing for this type of patient?

Langer:Probably the textbook answer is still no. But the thing is, you want to harvest the tissue. This patient, unfortunately, even in the area of durvalumab [Imfinzi], is likely to relapse. If they do, you want to know what the results are. And I foresee a day, not in the next year or 2—maybe 5 years, 8 years—when we will need to know and it will influence [treatment], so I think either answer is fine. By the book, there is no indication to test for genetic markers. We can debate PD-L1, but there’s no definitive indication.

Targeted Oncology:What are the treatment options for this patient?

Langer:Obviously, neoadjuvant chemotherapy, neoadjuvant chemotherapy/ radiation. This poor guy’s PFTs precludes chemotherapy with concurrent radiation. If he were older and frailer, I think we might choose sequential chemotherapy followed by radiation therapy.

Targeted Oncology:Which regimen would you use?

Langer:Lately, I pretty much use paclitaxel/carboplatin, but occasionally I’ve been using variations on cisplatin/pemetrexed and carbopl­atin/pemetrexed. Granted, it’s more expensive, and it’s no better than the etoposide/platinum. But in the back of my mind, I’m still giving systemic doses, which you’re not giving with weekly pacli­taxel/carboplatin. And if they [have nonsquamous disease], it is perfectly reasonable.

Case (continued):

The patient underwent therapy with cisplatin/etoposide and concurrent thoracic radiotherapy.Follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions. No evidence of distant spread was observed.

Targeted Oncology:Could he benefit from further therapy? How do you follow this patient?

Langer:Everyone is familiar with the PACIFIC trial that took the world, certainly took the lung cancer community, by storm 2 years ago. Personally, when this trial was conceived, I was very skeptical. Durvalumab had not yet been tested in a phase III [trial] or at least in advanced diseases, and it had no approval. Nivolumab [Opdivo], pembrolizumab [Keytruda], and frankly atezolizumab [Tecentriq] were ahead. But it was a wise move because [the investigators] figured the field was satu­rated in stage IV and in recurrent disease trials. Why not look at it in another setting? It was bold, and some thought it was foolhearted, but in retrospect, it was incredibly smart.

It was a randomized, double-blind, placebo-controlled phase III trial [in which durvalumab was administered following] concur­rent chemoradiation. They did not handcuff patients to a specific chemotherapy regimen; it could have been etoposide, paclitaxel/ carboplatin, but it had to be platinum based. They had to receive a minimum 50 Gy of radiation, which is actually a low dose of radi­ation. In North America, we use a minimum of 60 Gy. They had to have a good performance status [World Health Organization ≤1]; were stratified by age, sex, and smoking history; but were not strat­ified byEGFRor PD-L1 status, which is important to remember.¹

Its primary objective is PFS [progression-free survival]. The OS [overall survival] was a co-primary endpoint but was not available in the first report.1 This trial was tested in 713 patients, and the results were impressive—nearly 25% improvement in PFS at 18 months [49.5% vs 26.7%] and one of the most striking hazard ratios we’ve ever seen, at 0.51. This is from theNew England Journal of Medicinefrom last year.²This trial has the distinction of having 2 separateNew England Journal of Medicinearticles. I have never seen that happen before. First for the PFS data and the second for the OS data. At the 2019 ASCO Annual Meeting, there was a presentation for the [3-year OS update], and everything is holding up.³

Targeted Oncology:Do certain patients derive the greatest benefit from durvalumab consolidation? Do some patients see less benefit?

Langer:Looking at the forest plots, a benefit [is] seen across the board regardless of sex, age, and smoking status. Intriguingly, the smaller number of never smokers, for whatever reason, usually did better. Patients with stage IIIA disease did slightly better than those with IIIB disease. Patients with nonsquamous histology may have a rela­tively greater benefit, with a hazard ratio of 0.45. Analysis by PD-L1 status was interesting because the cutoff was 25%, not 1%. ByEGFRmutation status, a lot of people make hay about the confidence intervals, but it is in a small number of patients. There were only 43 patients out of 713 who hadEGFRmutations, less than 10% of those on the trial; but the hazard ratio is at 0.76, so you can make an argument, yes or no, to use it.4 We are completely divided at my institution. If they happen to know theEGFRstatus and they are positive for the mutations, some of my colleagues will absolutely not do it. Again, it is not a primary endpoint, and I have proposed the argument to those withEGFRmutations, this may be wrong. Again, this was an assessment using a few patients.

Rapid institution of durvalumab within 14 days after the completion of radiation, again, showed a relatively greater benefit, with a hazard ratio of 0.39. Remember, these folks had to get a scan as soon as they finished their chemoradiation, which deviates from our standard practice up until now. We were usually getting scans at 6 weeks, 8 weeks, or even 3 months later. The study has changed not only how we treat patients but also how we scan patients. You need it documented that at least there was no progression. You can do that with a cheap and easy scan.⁴

Until I saw the [Kaplan-Meier] curves for OS, I was on the fence about these data because this had purely a PFS endpoint initially. Remember, the clock started ticking on this study not in the beginning of chemoradiation but at the end. There is a lot of attrition; there are folks who did have progression or who would never have made it onto this trial. There are folks who had bad adverse effects or comorbidities who would not have made it on, but we don’t know what that percentage is because they were not screened at the beginning. [Rather], they were randomized after the chemoradiation was done.

In addition, PET scans were not a routine component of this trial. It was a global trial, and outside North America, Western Europe, and Japan, PET scans are not used routinely. Most of the time, it is just a plain, old CT scan, [whereas] we use PET scans routinely. When you get a PET scan on a patient with stage III disease, you know 20% of the time you are going to detect metas­tases that were otherwise occult on CT.

Targeted Oncology:Do you think giving him durvalumab or no treatment is better in this case? What are the clinical data to back it up?

Langer:Of course, I am going to do better. Any placebo trial versus an active agent will probably be a positive outcome, so I definitely had my skepticism. In this trial however, OS tracked PFS. There was an approximately 11.0% improvement at 24 months: 66.3% versus 55.6%. The placebo group is doing better or at least as well at the start of the trial, so we cannot blame a poorly performing placebo. According to Jhanelle E. Gray, MD, who [presented the updated data at ASCO], the 3-year absolute survival is still holding up at 57.0% of patients taking durvalumab versus 43.5%.³

References

1. Antonia SJ, Villegas A, Daniel D, et al; Pacific Investigators. Durvalumab after chemora­diotherapy in stage III non—small-cell lung cancer.N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937.
2. Antonia SJ, Villegas A, Daniel D, et al; Pacific Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med.2018;379(24):2342- 2350. doi: 10.1056/NEJMoa1809697.
3. Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial.J Clin Oncol. 2019;37(suppl 15; abstr 8526). doi: 10.1200/ JCO.2019.37.15_suppl.8526.
4. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo/controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC.Ann Oncol. 2017;28(suppl 5; abstr LBA1_PR). doi: 10.1093/annonc/mdx440.049.