Patel Considers a New Standard of Care When Treating Patients With NSCLC

Jyoti D. Patel, MD

Jyoti D. Patel, MD

Jyoti D. Patel, MD, recently shared the treatment considerations and decisions she makes when treating patients with non—small cell lung cancer (NSCLC). Patel, professor of medicine and director of thoracic oncology at the University of Chicago Medicine in Illinois, discussed her treatment considerations for patients with NSCLC based on case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion. His past medical history included hyperlipidemia, well-managed on simvastatin (Zocor); hypothyroidism, managed on levothyroxine (Synthroid); and chronic obstructive pulmonary disorder (COPD), managed on inhalers. He recently quit smoking, but had a prior 40-pack-year history. A Physical exam showed intermittent wheezing and ECOG performance status of 1. His creatinine clearance was within normal limits.

His chest CT revealed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes measuring 1.5 cm and 1.7 cm and moderate emphysema was noted. A PET confirmed the lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. His brain MRI was negative.

A pulmonary function test showed forced expiratory volume in the first second of expiration (FEV₁), 1.2; diffusing capacity of the lung for carbon monoxide (DLCO), 52%. A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. He was later staged at T2aN2M0, stage IIIa. Genetic testing was negative for known driver mutations.

What are your general impressions of this patient?

This is a 63-year-old man with a history of smoking who recently quit when he developed some cough and shortness of breath. He has been on inhalers for COPD and has some comorbidities, with a performance status of 1. Given his cough and shortness of breath, a CT was done, which showed a 3.1-cm right upper lobe mass, as well as mediastinal lymph nodes measuring 1.5 cm and 1.7 cm. A PET was done, which showed the lung lesion and mediastinal nodes without evidence of distant disease. He underwent an MRI of his brain, and pulmonary function test showed a decreased FEV₁of only 1.2 L and a DLCO of 52%. The pulmonologist performed a bronchoscopy that revealed adenocarcinoma in stations 4R and 7, and the contralateral 4L node was negative. Based on these findings, he has a stage IIIa NSCLC.

Do you typically order genetic testing for locally advanced lung cancer?

At our institution, we do genetic testing on these patients. This is clearly not a standard of care, but he didn’t have any known driver mutations. The testing has been primarily a research endeavor and has guided some of our patients to clinical trials previously.

What are the options for treatment for this patient?

Given that he has stage IIIa disease, he needs systemic and local therapy. However, based on the extent of mediastinal disease, COPD, and reduced lung function, it was felt that he was inoperable. He was then referred for concurrent chemotherapy and radiation.

In a patient with single-station disease and excellent performance status, sometimes we treat with neoadjuvant chemotherapy followed by resections, then followed by postoperative radiation therapy if there are N2 nodes. Many patients in the United States get treatment with neoadjuvant chemoradiation followed by resection. If we pull the National Comprehensive Cancer Network guidelines, these patients and their providers are equally divided, and much of it depends on access to board-certified thoracic surgeons early on.

Reasons for treating patients with just neoadjuvant chemotherapy rather than chemoradiation, followed by surgery, are to decrease radiation toxicity and maybe decrease the dose to unaffected lungs as well as the heart because you would be treating only the mediastinum.

Most patients with stage IIIa disease, however, are treated definitively with chemoradiation. That is primarily due to the extent of the disease and an inability to have meaningful resection and because of other comorbidities such as lung function.

Based on the extent of mediastinal disease and emphysema, the patient’s cancer was deemed inoperable. He was referred for consideration of concurrent chemotherapy and radiation. He underwent therapy with cisplatin/etoposide and concurrent thoracic radiotherapy and follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions.

Does the patient require further treatment?

The patient tolerated chemoradiation quite well. I believe the new standard of care, based on the PACIFIC data, is that the patient should get immunotherapy afterward with consolidation.¹

What did the PACIFIC trial show?

The PACIFIC trial was a phase III randomized study in which patients who had undergone chemoradiation were enrolled and then randomized after completion of treatment to either durvalumab (Imfinzi) for 12 months or placebo.

There were 2 coprimary endpoints, progression-free survival (PFS) and overall survival (OS). Patients were well matched in both arms, and the trial was significantly positive for PFS. The hazard ratio was 0.52, favoring durvalumab. At 12 months, the PFS was 56% versus 35% in the placebo arm. At 18 months, it was 44% versus 27%. The curves look like they leveled out, but we await OS data. That should be presented at a meeting in the near future. But based on this magnitude of benefit for PFS, I think this is a new standard of care.

When would you start your patients on durvalumab?

You should generally start the immunotherapy as soon as possible. That is based on an analysis of the PACIFIC trial, in which patients were started between 1 and 42 days after concurrent chemoradiation. There was a trend toward better survival for patients who were started within the first 2 weeks. We will see how that pans out. But generally, if patients are well and don’t have toxicity, I tend to start earlier. But the fact is, many patients do have some toxicity after chemoradiation. In the real world, we end up waiting several weeks.

How do you follow this patient?

In the PACIFIC study, patients underwent CT scans periodically, every 3 months. I would do the same and follow, as I have for patients who are undergoing chemoradiation. Maybe I wouldn’t get a scan right after chemotherapy and radiation, but maybe wait until those 3 months and then follow them for that first year of therapy 2 to 3 months with imaging. And then [every 4 to 6 months] as we get further out from their treatment.

I think it’s important to note that not only do patients have less PFS, but they also have decreased central nervous system relapse. That was a significant benefit. Additionally, I think we were quite worried about giving immune checkpoint inhibitors after chemoradiation because it could potentiate pneumonitis. But in general, this is very well tolerated. The levels of grade 3 pneumonitis were not significantly different between the arms.

How would you manage the toxicities associated with durvalumab?

One needs to be cognizant of potential toxicities. This means being vigilant about subtle symptoms, such as shortness of breath, cough, and fever. If a patient did develop any pulmonary symptoms, that would suggest the need to perform rapid imaging of these patients with CT scans, referral to pulmonology, holding of the drug, and initiation of steroids as appropriate.

Case 2

An 81-year-old man presented with symptoms of coughing, dyspnea, upper back pain, and fatigue requiring frequent rest. His past medical history revealed hypercholesterolemia, controlled on pravastatin (Pravachol); hypertension, controlled on verapamil (Verelan); psoriatic arthritis, for which he was not on treatment for 3-plus years. He was a former smoker, but was physically active and played golf weekly. He had an ECOG performance status of 1.

A chest CT revealed a 2.5-cm solid mass in the left upper lobe and lymphadenopathy in the left hilar and bilateral mediastinal nodes and bilateral, small pulmonary nodules, with the largest one 8 mm. Further PET/CT imaging showed 18F-FDG uptake in the lung mass, the left hilar, both mediastinal lymph nodes, and the thoracic spine (T5/T6).

A bronchoscopy and transbronchial lung biopsy were performed. His pathology later showed grade III squamous cell carcinoma PD-L1 expression by immunohistochemistry 22C3; tumor proportion score, 65%. He was diagnosed with stage IV squamous NSCLC.

What are your general impressions of this patient?

This is an 81-year-old patient who has a history of psoriatic arthritis, for which he’s been off treatment for over 3 years. He also has some hypertension and hypercholesterolemia, quit smoking years ago, and remains physically active, with a performance status of 1. He had back pain and cough, so he underwent a CT screening that showed a left upper lobe mass and multiple bilateral small pulmonary nodules. A PET scan demonstrated uptake in all these nodules, mediastinal nodes, as well as the thoracic spine. He underwent a bronchoscopy that showed a poorly differentiated squamous cell carcinoma. He had PD-L1 expression, greater than 50%, and received a diagnosis of stage IV squamous NSCLC.

What is the prognosis for this patient?

Previously, a gentleman such as him would have a prognosis of about 8 to 10 months based on earlier trials. There were no significant improvements with histology-specific chemotherapies, and targeted therapies with vascular endothelial growth factor inhibitors were not safe to use in these patients. So patients were treated with chemotherapy alone. However, with the advent of checkpoint inhibitors, prognosis has changed significantly in patients with high PD-L1 expression. Based on that alone, he would be a candidate for monotherapy with pembrolizumab (Keytruda). We also received exciting data from the 2018 ASCO Annual Meeting for the combination of pembrolizumab with chemotherapy, as well as atezolizumab (Tecentriq) with chemotherapy in patients [with squamous disease], which make this approach quite desirable.

The confounding factor for this gentleman is that he has autoimmune arthritis, so he has a history of psoriatic arthritis. These patients have not been included in clinical trials. However, given that there are trials now looking at comorbidities or institutional experiences, I think many of us feel comfortable talking to our patients about the risk and benefit of these agents. Because he has been minimally symptomatic and it has been several years since he last required any therapy for his psoriatic arthritis, it is reasonable to consider pembrolizumab monotherapy for this gentleman. In speaking with him, it became very clear that he wanted to preserve quality of life and was interested in monotherapy.

Are you routinely testing for PD-L1 expression in patients with newly diagnosed disease such as this one?

Testing for PD-L1 is now standard of care for all patients with NSCLC. It can often be done in-house within 24 hours, and often we will get the PD-L1 information before genotyping in nonsquamous tumors. But certainly, for patients with squamous cell tumors, after PD-L1, I don’t think testing beyond that is required unless the clinical scenario dictates that.

What are the treatment options you would consider?

Given his high PD-L1 expression of greater than 50%, based on KEYNOTE-024, he could undergo treatment with mono-agent pembrolizumab versus chemotherapy.²That study demonstrated a significant improvement in PFS for patients, with a hazard ratio of 0.50. I think that is truly exciting. The response rate also improved.

Now that we have data looking at all-comers treated with chemotherapy and pembrolizumab, there is growing acceptance that chemotherapy plus immuno-oncology therapy could also be appropriate in this patient population. My take on it is that if the patient doesn’t have critical disease, single-agent pembrolizumab would be very reasonable. However, for patients who are very symptomatic, there are several trials now that support chemo-immunotherapy.

Is there a potential role for radiation therapy to address his symptoms of dyspnea and back pain?

Absolutely. If he is having painful back metastases, he can have improvement in his functional status by treating his pain. Moreover, there have been a couple of series, as well as posttrial analyses, that suggest that immune checkpoint inhibitors tend to be particularly effective after radiation. That may be due to neoadjuvant presentation or shifting to a less immunosuppressive environment.

The patient was started on treatment with pembrolizumab.

How does his older age and good performance status factor into the choice of pembrolizumab?

Patient-centric decision making is very important for a patient to maintain his or her independence and decrease the level of toxicity. However, for anyone with high PD-L expression, I think it would be very reasonable to consider pembrolizumab alone.

Do precautions need to be taken considering his psoriatic arthritis?

Absolutely. The discussion regarding toxicity is one that comes with a lot of uncertainty, but just watching him closely is important, to look for a flare in symptoms. Autoimmune disorders are important to watch for in all these patients. We routinely check thyroid function and routinely ask for a long and complicated review assistance. Everything from shortness of breath to diarrhea to changes in energy is often a clue that patients are having more toxicity than we initially expect.

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. Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Presented at: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 17.06.