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How to Best Use Immunotherapy Combinations for Lung Cancer

Fuerst, Mark L.

doi: 10.1097/01.COT.0000480387.52262.c5
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NEW YORK—Two recent approvals of checkpoint inhibitors mark the crest of a new wave of immune therapies for lung cancer patients, and the next step now is to determine how to best combine the therapies—a topic that was explored in a session at the Chemotherapy Foundation Symposium here.

The anti-programmed cell death 1 (PD1)-antibody nivolumab (Opdivo) was approved for squamous non-small cell lung cancer (NSCLC) in March and then received expanded approval for non-squamous NSCLC in October to treat patients with metastatic disease that progressed during or after platinum-based chemotherapy.

Also receiving approval in October was another PD1 inhibitor, Pembrolizumab (Keytruda), granted accelerated approval to treat NSCLC patients with advanced disease that progressed after other treatments and with tumors that express programmed death-ligand 1 (PD-L1).

With multiple drug options, clinicians need to determine how to choose the most appropriate therapy for their NSCLC patients, said Heather Wakelee, MD, Associate Professor of Medicine (Oncology) at Stanford University Medical Center. “We need to move beyond second-line or third-line chemotherapies.”

The future holds promise with combinations of chemotherapy with targeted therapies, other immune regulatory drugs, and radiation. A better understanding of PD-L1 and other biomarkers may lead to other strategies, such as vaccines and adoptive immunotherapy strategies.

First-line trials of PD-1 or PD-L1 inhibitors versus chemotherapy have been completed, with the results eagerly awaited, she noted. Adjuvant trials of PD-1 and PD-L1 inhibitors are open or in planning phases. “Until we have the data we should not assume we will see the same benefit in these settings as we have seen in the second-line setting. Anti-PDL1 drugs are being tested in Phase III trials. I urge caution with their first-line use now.”

The future may lie in combination regimens, such as the additions of chemotherapy to targeted therapy. Wakelee noted that the combination of carbo-platin plus atezolizumab shows an overall response rate of about 50 percent, which is similar to that of carboplatin alone. Carboplatin plus pembroliz-umab shows a 76 percent response.

“Multiple, ongoing targeted therapy combination trials are looking at epidermal growth factor receptor inhibitors, mitogen-activated protein kinase inhibitors, MET inhibitors, and many others,” Wakelee continued.

Small trials of pembrolizumab plus ipilimumab and nivolumab plus ipilimumab show promising responses, but these combinations may lead to stronger autoimmune responses. Ipilimumab may not need to be given as frequently and can be given intermittently.

In the CheckMate 021 trial, the combination of nivolumab and ipilimumab led to a 48 percent response rate in patients who showed PDL1 expression.

In other thoracic malignancies, pembrolizumab shows very encouraging single-agent activity in small cell disease (28% response rate) and in mesothelioma (29% response rate), she said.

In small-cell disease, the CheckMate 032 trial showed that median overall survival doubled with nivolumab plus ipilimumab (8.2 months) compared with use of nivolumab alone (4.4 months).

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Biomarkers to Predict Response

PD-L1 expression is a promising predictive marker for response and benefit with the PD-1 and PD-L1 inhibitors, she said. “There is a good response of 30 to 40 percent in patients with PD-L1 expression. “But there is a 10 percent response in patients with no expression, which is better than second-line chemotherapy. So we should not exclude patients who have negative expression.”

There is no consensus on the ideal analysis as yet, and there are questions on which antibody to use for detection, what constitutes “positivity,” which cells to analyze—tumor cells, tumor-infiltrating lymphocytes, or both.

Other markers may be helpful to determine the mutational burden. An ongoing project of the International Association for the Study of Lung Cancer will help clarify these issues, especially with PD-L1, she said. “The goal is to prospectively identify patients who are most likely to benefit without excluding therapy to those with small but meaningful hope.”

Overall response by PD-L1 expression with atezolizumab or nivolumab shows a “high” 32 percent response for those with expression versus eight percent for patients with no expression, she said.

Her roadmap to other strategies also includes tumor-draining lymph nodes, interleukin-2, and co-culture with dendritic cells. And, she said, there is encouraging data with radiation therapy: “With two immune therapies just approved, the paradigm is shifting. But we still don't understand how to select which one to use. In five years, we will have a better understanding of combination regimens. There is no reason why we cannot get a combination for everyone. A 20 percent response rate is good, but not phenomenal.

“We all have patients on immunotherapy for a long time,” Wakelee continued. “We have some patients with targeted mutations on therapy for more than five years. Smarter immune combinations will kick up the response without killing the patient or inducing autoimmune responses.”

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Incorporating Immunotherapies into Treatment

Another speaker at the session, Edward B. Garon, MD, MS, Associate Professor in the Department of Medicine, Hematology & Oncology at David Geffen School of Medicine at UCLA, called the safety profile of the two approved PD-1 inhibitors “generally good but with some serious toxicities.”

Studies show that nivolumab monotherapy has a response rate of about 17 percent, with median progression-free survival (PFS) of less than two months. “What's exciting is that the median duration of response is 74 weeks. Patients who are doing well appear to do very well,” he said. New data show 18 percent survival at three years with nivolumab.

The CheckMate 017 trial shows a PFS advantage for nivolumab over docetaxel in squamous cell disease, and a three-month overall survival benefit, “which we are not used to seeing in lung cancer,” Garon said. “Not only is there a response improvement with nivolumab, but among those who responded, they are twice as likely to have ongoing responses.”

Similarly, for patients in the CheckMate 057 trial of non-squamous cell disease, median overall survival was about three months longer with nivolumab as compared with docetaxel.

In general, anti-PD1-antibodies are well tolerated, with pneumonitis the most frequent adverse event, Garon noted. The rate of pneumonitis is less than five percent, but many cases are high grade and thus still a concern—“If you suspect pneumonitis, start the patient on high-dose steroids,” he said, adding that immune-related toxicity is tolerable, including hypothyroidism, which is easily managed.

He agreed with Wakelee that malignancies with higher mutational load appear to be more sensitive to therapy. In the KEYNOTE-001 trial, for example, about one-quarter of the initial responses to pembrolizumab were seen in patients with the highest PD1 expression.

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Combinations and Sequences

“We have a host of active agents that are still active in conjunction with PD-L1 and PD1 inhibitors,” said the third speaker in the session, Suresh S. Ramalingam, MD, Professor and Director of Medical Oncology at Emory University. “Many combinations are being tested in early-phase clinical trials so we can understand the interactions between treatment modalities in greater depth.”

He described the rationale for combining cabozantinib with nivolumab in NSCLC: More than half of NSCLC patients have disease progression on nivolumab within the first three months of therapy. Cabozantinib has shown immunostimulatory properties in other tumors, and a Phase II study has been proposed to test the combination of cabozantinib and nivolumab against use of nivolumab alone in NSCLC.

Ramalingam highlighted the relevant clinical issues for combinations, including toxicity, concurrent or sequential therapy, use in curative settings, and whether the biomarker is common or variable. “What is the optimal way to combine chemotherapy with immunotherapy?” he asked. “Can sequential use capitalize on enhanced antigen release following chemotherapy?”

In conclusion, Ramalingam said: “Combination approaches are promising next steps for immune checkpoint inhibitors. Evaluation in curative settings is of high priority. Lung cancer is ideally suited for studying this class of agents due to the high mutational burden.”

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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