Durvalumab Shows Promise in Patients With NSCLC, Brahmer Says

Julie Brahmer, MD

Julie Brahmer, MD

Julie Brahmer, MD, recently shared the treatment considerations and decisions she makes when treating patients with non—small cell lung cancer (NSCLC). Brahmer, co-director of the Upper Aerodigestive Department, Johns Hopkins Hospital, in Baltimore, Maryland, discussed her treatment considerations based on case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

An 81-year-old man presented with symptoms of coughing, dyspnea, upper back pain, and fatigue requiring frequent rest. His past medical history included hypercholesterolemia, controlled on pravastatin (Pravachol); hypertension, which was controlled on verapamil (Verelan); and psoriatic arthritis, 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 (PS) of 1.

A chest CT revealed a 2.5-cm solid mass in the left upper lobe, lymphadenopathy in the left hilar and bilateral mediastinal nodes, and bilateral small pulmonary nodules, with the large one 8 mm. His PET/CT imaging showed¹⁸F-FDG uptake in the lung mass, left hilar, both mediastinal lymph nodes, and thoracic spine (T5/T6).

A bronchoscopy and transbronchial lung biopsy were performed. Pathology showed grade 3 squamous cell carcinoma PD-L1 expression by immunohistochemistry (IHC) 22C3 assay, tumor proportion score (TPS) of 65%. He was diagnosed with stage IV squamous NSCLC.

Targeted Oncology:What are your general impressions of this patient?

Brahmer:This is an 81-year-old man who presents with cough, shortness of breath, back pain, and fatigue. He does have other health issues, including hypertension, hyperlipidemia, and psoriatic arthritis, although it had not required treatment for at least 3 years. He is a former smoker, yet he is very active, with an ECOG PS of 1.

He was found to have a 2.5-cm mass in the left upper lob, as well as a left hilar and mediastinal adenopathy and bilateral small pulmonary nodules. The PET scan showed the same, as well as metastasis to the thoracic spine. A biopsy of the lung revealed a stem cell carcinoma; PD-L1 expression using the 22C3 IHC assay revealed a TPS of 65%. He was then diagnosed with stage IV squamous carcinoma with high PD-L1 expression.

What is the prognosis for this patient?

Typically, in the past, we would treat this patient with chemotherapy for a [median of] 9, to up to 12, months. But now, patients who have high PD-L1, if they receive single-agent immunotherapy such as pembrolizumab (Keytruda), the prognosis in the patient can be quite good. Even, on average, up to 32 months.

For this patient, the treatment options include palliative radiation to the back, as well as chemotherapy. Right now, the main recommendation, since his tumor has a high TPS for PD-L1, would be a PD-1 inhibitor, which is pembrolizumab. If there is some reason we are concerned about giving immunotherapy, you can also give combination chemotherapy, either gemcitabine/cisplatin or paclitaxel/carboplatin. But even in this patient with a history of psoriatic arthritis, I would feel comfortable putting him on single-agent pembrolizumab based on the KEYNOTE data.

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

Yes, I am routinely testing in patients with metastatic disease.

The patient was started on pembrolizumab.

What is the expected experience with pembrolizumab in terms of outcomes and adverse events?

In general, pembrolizumab is [easily] tolerated. [Adverse effects] are mainly fatigue. The patient may have some hypothyroidism, rash, and diarrhea that can occur. The overall survival (OS) is very good and tends to favor pembrolizumab. We know that there is approximately a 30-month median survival in patients with high TPSs with PD-L1 who receive pembrolizumab. If they receive chemotherapy, the median OS is approximately 14 months in this group. All patient can benefit from this if they have high PD-L1. Those who are previous smokers, have a good PS, or have any type of histology can all benefit from pembrolizumab.

How does his older age and good PS factor into this choice?

His PS tends to favor him trying some form of treatment. If he had a poor PS, with an ECOG PS of 2 or worse, it is unclear that this type of therapy would benefit him since most of the clinical trials required an ECOG PS score of 0 or 1.

From an age standpoint, at least per the KEYNOTE-024 trial, using a cut-off of 65 years of age, there was no difference in OS improvement.²We don't know if the older patients, at least above 75, also benefit. People are looking at this, and depending on the cancer, there is some question as to whether or not these patients who are older benefit from immunotherapy. They may have a dampened immune response, as your immune system ages. But we have patients in our clinic who are older and do have a good response to immunotherapy, specifically PD-1 or PD-L1 blockade. I would not use age as criteria to start with pembrolizumab versus chemotherapy. I think pembrolizumab is at least much easier to tolerate in these patients right now compared with chemotherapy.

Do precautions need to be taken considering his psoriatic arthritis?

With a psoriatic arthritis that is not requiring treatment over the past 3 years, it is worth the risk of pembrolizumab because he would be less likely to have a flare. It is something that you have to keep in mind. If he came to my clinic with psoriatic arthritis requiring active treatment to keep it under control, that would be a much more in-depth conversation about the fact that this immunotherapy could make that worse while were trying to treat the cancer.

Case 2

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

A chest x-ray showed opacity in the lung right upper lobe and a 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; moderate emphysema noted. A PET confirmed the lung lesion and mediastinal lymphadenopathy, without evidence of distant metastases. His brain MRI was negative.

A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. Genetic testing was performed and proved negative for known driver mutations. His staging was T2aN2M0, stage IIIa.

What are your general impressions of this patient?

This is a 63-year-old smoker, with a new diagnosis of stage IIIa adenocarcinoma without known driver mutations. On the scan, he has enlarged mediastinal lymph nodes. So, I would not think that he has potentially resectable disease after neoadjuvant therapy. Based on that, we typically would recommend chemotherapy given concurrently with radiation therapy.

What are the options for treatment?

Because he has enlarged lymph nodes on a CT scan, this is not microscopic disease. We typically say that when patients have enlarged lymph nodes on scan, they would not be eligible for neoadjuvant therapy. Neoadjuvant therapy is for patients with microscopic disease or [those who are] only positive on PET. In the case of this patient, we would recommend concurrent chemotherapy and radiation.

If the patient had normal-sized lymph nodes, then we would consider chemotherapy and radiation [as] the neoadjuvant therapy. The thinking is that the chemotherapy and radiation may clear those lymph nodes so that he would be able to undergo surgery. Some people do neoadjuvant chemotherapy, but there is no [for a] head-to-head comparison between the 2. It depends on your team and what your team may link to. But in this case, I would say that his disease is not potentially resectable because he does have enlarged mediastinal lymph nodes on scan.

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

Does the patient require further treatment?

His physicians agreed with my previous decision and gave him concurrent cisplatin/etoposide with radiation. After this was completed, on repeat scans he did have a partial response and his tumors decreased in size.

Based on the PACIFIC trial, comparing consolidation durvalumab (Imfinzi) versus no consolidation or placebo, we would recommend durvalumab after concurrent chemotherapy and radiation.¹The trial enrolled patients with stage III disease who were not resectable and had not progressed following definitive chemotherapy and radiation therapy. They were randomized within 42 days of completing chemotherapy and radiation to either durvalumab at 10 mg once every 2 weeks for up 6 months or placebo. The randomization was 2:1, with 2 primary endpoints of progression-free survival (PFS) and overall survival. In the data that [were] presented, we do have PFS findings.

Looking at baseline characteristics from the trial, in general they were well balanced. There were very similar numbers of squamous and nonsquamous histology. Most of the patients were former or current smokers. There were about half at stage IIIa and half at stage IIIb disease. Twenty-six percent to 29% of patients received induction chemotherapy followed by concurrent chemotherapy and radiation. The majority of patients had received 54 Gy to 66 Gy prior radiation therapy.

In general, the majority of the patients did respond to the initial concurrent chemotherapy and radiation with at least a partial response.Approximately 43% of patients completed 12 months of their observation on durvalumab versus 30% on placebo. The majority of reasons why patients discontinued was mainly due to either disease worsening and side effects. A little more than 15% stopped due to adverse events (AEs) with durvalumab, and a little under 10% stopped treatment on the placebo arm.

Approximately 30% of patients received subsequent therapy after stopping on durvalumab versus 43% on the placebo. This was with a 14.5-month follow-up time. We know that the PFS was better for those patients on durvalumab after concurrent chemotherapy and radiation, with a hazard ratio of 0.52, which was statistically significant. We see an 18-month PFS rate of 44% in patients who received durvalumab versus 27% in those patients who received placebo. The objective response [rate in] the durvalumab arm was 28% versus 16% on placebo. The duration of response had not been reached yet at the time of manuscript for the durvalumab arm. However, for the placebo arm, it was reached at 13.8 months.

Most patients did benefit from receiving durvalumab, except for patients who hadEGFRmutations—although the number of patients were quite low on the durvalumab arm. There were only 29 patients who hadEGFR-mutant disease versus 14 patients on the placebo arm. Also to note, the time until metastases or death was much longer if you received durvalumab compared [with] placebo.

Were there any toxicities to note from this trial?

In general, people are concerned about these types of inhibitors after radiation therapy, but we did not see an increase in all-cause AEs. If you look specifically at any grade 2-related AEs, on the durvalumab arm, about 68% of patients had any-grade treatment-related AEs versus 53% in the placebo arm. If you look at immune-specific AEs, this was higher on the durvalumab arm of 24% versus 8% on the placebo arm. But significant AEs that required treatment, such as steroids, for grade 3 or 4 immune-related AEs [were] about the same for both arms. We are always worried about pneumonitis after radiation therapy, and there was a slight trend of any-grade pneumonitis on the durvalumab arm, occurring in about 34% of patients versus 25% in the placebo arm. However, significant pneumonitis, grade 3 or 4, was roughly the same on both arms.

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: the IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 17.06.