Immune Checkpoint Inhibitors Offer New Hope for Patients with Lung Cancer

Lung cancer remains the leading cause of cancer-related deaths in men and women, accounting for 1 in every 4 deaths caused by cancer in the United States. However, recent advances in immunotherapy, especially those called “immune checkpoint inhibitors,” bring new hope for patients with lung cancer.

Currently, the main advances in immunotherapy for patients with lung cancer relate to patients with the most common type of lung cancer—non–small-cell lung cancer (NSCLC). Several immune checkpoint inhibitors are now approved for patients with NSCLC and are giving hope to patients living with this disease.

In addition, researchers are continuing to study other options with immunotherapies for lung cancer, including the use of 2 or more immunotherapies together, or the use of immunotherapy with other drugs or with chemotherapies, with the hope that these combinations will result in even better outcomes for patients.

One of the main dilemmas for doctors who treat patients with lung cancer is deciding who will benefit most from which treatment strategy. Recent studies discussing immune checkpoint inhibitors for lung cancer focused on this problem.

Joan H. Schiller, MD, Professor and Chief of the Hematology/Oncology Division at the University of Texas Southwestern Medical Center in Dallas recently wrote an editorial on the new treatments for patients with advanced lung cancer, focusing on the role of immunotherapies in the treatment of patients with lung cancer, and highlighting recent advances with immune checkpoint inhibitors.¹

“The next breakthrough in the treatment of NSCLC was the development of immune check point inhibitors—antibodies that target the programmed death 1 (PD-1) pathway,”¹ Dr. Schiller wrote. However, she pointed out, “Many unanswered questions remain, perhaps the most significant of which is how to predict which patients are likely to benefit from immune checkpoint inhibitors,”¹ she added.

Immune Checkpoint Inhibitors for Lung Cancer

Immune checkpoint inhibitors are therapies that “release the brakes” on the immune system, allowing the body’s immune system to destroy cancer cells. However, immunotherapy does not work for every patient with lung cancer.

The checkpoint inhibitors that target the PD-1 and PD-L1 protein (that binds to the PD-1 checkpoint) are showing good results in about one-third of patients with NSCLC.

So far, 4 immune checkpoint inhibitors have been approved by the FDA for the treatment of patients with NSCLC, and another checkpoint inhibitor, the CTLA-4, is being investigated, in combination with another checkpoint inhibitor, as a potential treatment for patients with NSCLC.

Opdivo (nivolumab). The anti-PD-1 checkpoint inhibitor Opdivo is approved for patients with squamous, advanced or metastatic (spreading) NSCLC that progressed during or after chemotherapy, as well as for patients with nonsquamous NSCLC. Opdivo is also approved for the treatment, after treatment with other therapies, of patients with NSCLC that is associated with the EGFR or ALK gene mutation.

In a new study, Opdivo therapy led to major responses to treatment in almost half of the patients who had early-stage NSCLC who received this checkpoint inhibitor before surgery to remove the cancer.²

According to the researchers, treatment with Opdivo reduced the lung cancer significantly and was associated with only a few side effects. In some patients, this treatment also reduced the risk that the cancer will come back.²

Keytruda (pembrolizumab). Another anti-PD-1 checkpoint inhibitor is Keytruda, which is approved for the treatment of patients with metastatic NSCLC. Keytruda was first approved for patients with NSCLC and PD-L1 expression plus the EGFR or ALK mutation, which progressed during or after standard chemotherapy.

Keytruda was also the first checkpoint inhibitor to be approved by the FDA as first-line treatment for patients with NSCLC and high PD-L1 expression. Patients with high PD-L1 expression who receive Keytruda have even longer survival than those with low PD-L1 expression.

Keytruda is also approved as the first treatment, in combination with chemotherapy, for patients with metastatic, nonsquamous NSCLC.

Tecentriq (atezolizumab). Yet another anti-PD-1 checkpoint inhibitor immunotherapy approved for NSCLC is Tecentriq, which is used in patients with metastatic NSCLC that progressed during or after standard chemotherapy.

Patients with NSCLC and an EGFR or ALK mutation can be treated with Tecentriq if their cancer progresses after appropriate therapy with other drugs.

Imfinzi (durvalumab). The most recently approved anti-PD-1 checkpoint inhibitor is Imfinzi, which is approved by the FDA for the treatment of patients with advanced NSCLC that can’t be removed by surgery and did not progress after use of chemotherapy plus radiation therapy.

Yervoy (ipilimumab). A different type of checkpoint inhibitor, Yervoy targets the CTLA-4 protein and is currently being studied for use in combination with Opdivo for the treatment of patients with NSCLC. (Yervoy is currently approved for patients with metastatic melanoma but not for lung cancer.)

Immunotherapy Combination in Lung Cancer

Researchers are now studying the use of 2 immunotherapies together as a new option that may show better outcomes than just 1 immunotherapy in patients with NSCLC. A new study compared the use of the 2 immunotherapies—Opdivo and Yervoy—versus chemotherapy in patients with advanced NSCLC and high tumor mutational burden (TMB), a new biomarker for how many mutations the patient’s cancer has.

The results showed that patients with the TMB biomarker who received the 2 immunotherapies together had a significantly longer time without tumor progression, or progression-free survival, than those who received chemotherapy as the first treatment.³ In addition, the immunotherapy combination had few or no serious side effects.

“Halving the risk of death is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations.”

—Leena Gandhi, MD, PhD

“The immunotherapy combination improved progression-free survival independent of histology type (squamous or nonsquamous) and PD-L1 expression,” said Matthew D. Hellmann, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York City, at the 2018 American Association for Cancer Research (AACR) meeting.

“The breadth, duration, and depth of response were all substantially improved by the immunotherapy combination, with a more than tripling of the 1-year progression-free survival with the immunotherapy combination,” Dr. Hellmann said, adding that there was a clear suggestion that the combination of the 2 immunotherapies results in longer survival.

According to Dr. Hellmann and his colleagues, the results of this study confirm the benefits of using Opdivo in combination with Yervoy in patients with NSCLC, especially in those with the TMB biomarker.³

Immunotherapy plus Chemotherapy in Lung Cancer

Another treatment option that was recently introduced for patients with lung cancer is the combination of immunotherapy plus chemotherapy as the first option for patients with advanced NSCLC. In a recent study, researchers compared the use of Keytruda plus chemotherapy versus chemotherapy alone as the first treatment for patients with metastatic, nonsquamous NSCLC (and no EGFR or ALK mutation).

This study led to the approval of Keytruda, in combination with chemotherapy, as the first treatment for patients with metastatic, nonsquamous NSCLC. The study showed that adding immunotherapy to chemotherapy doubled the survival time compared with chemotherapy alone.⁴

“Halving the risk of death is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations,” said Leena Gandhi, MD, PhD, Director of the Thoracic Medical Oncology Program at Perlmutter Cancer Center in New York City, at the 2018 AACR meeting.

“In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab [Keytruda] to standard chemotherapy with pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone,” Dr. Gandhi said.

“Pembrolizumab plus pemetrexed and platinum may be a new standard of care for first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression,” Dr. Gandhi said, adding that today, most patients with nonsquamous NSCLC routinely get tested for PD-L1.

Commenting on this study at the AACR meeting, Roy S. Herbst, MD, MS, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, said that this new combination will change the way patients with NSCLC are being treated.

“This randomized phase 3 trial sets a new standard. The results of this trial quite frankly exceeded expectations,” Dr. Herbst said.

References

1. Schiller JH. A new standard of care for advanced lung cancer. New England Journal of Medicine. 2018;378:2135-2137.
2. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. New England Journal of Medicine. 2018;378:1976-1986.
3. Hellmann MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. New England Journal of Medicine. 2018;378:2093-2104.
4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. New England Journal of Medicine. 2018;378:2078-2092.