Immunotherapies Target PD-1 pathway for Non-Small Cell Lung Cancer

At a Glance

  • Nivolumab, pembrolizumab and atezolizumab are FDA approved treatments for advanced non-small cell lung cancer and help about 20% of patients.
  • Tumor sequencing research allows us to understand why patients do and do not respond and predict response to immunotherapy.
  • Research combining PD-1 pathway inhibition with other immunotherapy agents, chemotherapy and radiation are active areas of research to help more patients with lung cancer.

"‘Groundbreaking’ and ‘revolutionary’ often overstate the case, but they truly apply to the impact of the new immunotherapy agents that target the PD-1 pathway for non-small cell lung cancer."

— Dr. Naiyer A. Rizvi

Lung cancer is one of the most common cancers in both men and women worldwide, accounting for 13 percent of newly diagnosed cancers. Approximately 85 percent of all lung cancers are characterized as non-small cell lung cancer (NSCLC).

A major development in thoracic oncology in recent years has been the FDA approval of a new class of immunotherapies called immune checkpoint inhibitors for the treatment of NSCLC. Research by Dr. Naiyer A. Rizvi, Director of Thoracic Oncology and Co-Director of Cancer Immunotherapy at NewYork-Presbyterian/Columbia University Irving Medical Center has been integral to the approval of these agents.

Nivolumab, pembrolizumab and atezolizumab block the PD-1 pathway by disabling the interaction between PD-1 protein on T cells and PD-L1 on tumor cells. This restores T-cell recognition of cancer as “foreign,” leading to T-cell destruction of cancer cells.

Sequencing Tumor DNA to Predict Response

Dr. Rizvi’s research has shown how the genetic code of a lung cancer tumor can be analyzed to determine whether a patient will respond to immunotherapy or not. His research continues to study the genetic basis of sensitivity and resistance to immunotherapy supported by funding from the NIH (1R01CA205426).

During Dr. Rizvi’s research, he hypothesized that the cancers that had accumulated the greatest DNA damage were more likely to have depleted the immune system and therefore more likely to be helped by PD-1 inhibitors.

Using advances in sequencing technology to study the entire exome of tumors from patients with NSCLC who were treated with another PD-1 inhibitor, pembrolizumab (Keytruda®), he and his team confirmed that the more genetically damaged the tumor, the more likely the patient was to respond to PD-1 inhibitors.

Before and after treatment with anti-PD-L1 immunotherapy

Before and after treatment with anti-PD-L1 immunotherapy

The research was an important first step toward being able to predict who will respond to PD-1 inhibitors and offered a new way of thinking about precision medicine based on the sequencing of tumor DNA.

Immunotherapy Combinations

Dr. Rizvi and his team are also studying other immunotherapy combinations that can harness the immune system more effectively . They recently published preliminary data in The Lancet Oncology, with a combination of PD-L1 and CTLA-4 blockade showing the this combination could be more effective than single agent blockade of the PD-1 pathway. To further study this preliminary result, Dr. Rizvi is the international study chair of a phase 3 trial (NCT02453282) with this combination versus standard chemotherapy administered as first line treatment for advanced non-small cell lung cancer that could change the landscape of how we treat lung cancer.

Immunotherapy Plus Radiation

Dr. Silvia Formenti, Radiation Oncologist-in-Chief at NewYork-Presbyterian/Weill Cornell Medical Center and Chair, Department of Radiation Oncology, Weill Cornell Medicine is leading a multidisciplinary team of researchers, physicists, technicians and clinicians to change the radiation treatment paradigm, from ablating the tumor to converting the tumor into an individualized vaccine, in the context of cancer immunotherapy.

They have translated preclinical work into clinical trials in NSCLC, metastatic breast cancer and other cancers, and have also used radiotherapy as an adjuvant to immunotherapy of solid tumors and lymphomas. They are now working to determine best dose combinations, fractionation schedule and patient selection criteria.

“Our findings have ‘repositioned’ radiation therapy in a novel application, that of an immune modulator. With the advantage of its very focused and localized nature, radiation is ideal for combination with systemic modulations of the immune system” Dr. Formenti said. “Immunotherapy is at the forefront of precision oncology, and radiation will play an important role in this process.”

Also at Weill Cornell Medicine, Dr. Nasser K. Altorki, Chief of Thoracic Surgery, and Dr. Formenti are conducting a unique window of opportunity Phase II clinical trial to evaluate the clinical benefits associated with non-ablative radiation given concurrently with an immune checkpoint inhibitor in early stage lung cancer. The purpose of the trial is to assess whether low dose radiation can enhance the effect of immunotherapy in patients with early stage lung cancer and reduce the frequency of cancer recurrence.

“Understanding how cancer cells can subvert the cells of the immune system allows us to design treatments that either prevent or reverse these events and restore the capacity of the immune cells to kill the cancer,” said Dr. Altorki.

Immunotherapy Plus Chemotherapy Trial

An underexplored area has been the application of immunotherapy to locally advanced but resectable lung cancer. Because of the propensity of these tumors to spread early and have micrometastases early, long-term survival
is still relatively limited. We have improved outcomes in these patients by giving chemotherapy before or after surgery however there remains a need to improve the cure rate in these patients. By delivering both chemotherapy and immunotherapy together preoperatively, Dr. Rizvi hopes to increase survivorship for patients with resectable lung cancer. This is the only such trial (NCT02716038) being conducted as preoperative or neoadjuvant strategy for NSCLC and is underway at Columbia University Medical Center.

“Patients have read about the promise of immunotherapy, and they are eager to try this approach,” says Dr. Catherine Shu, the principal investigator at Columbia. “But at the moment, these PD-1/PD-L1 inhibitors are only available for those with Stage 4 metastatic disease. This trial is a way for patients with earlier stage disease to have access to immunotherapy.”

The plan for all patients is to proceed to surgery after this induction treatment. Patients enrolled in this trial will receive nab-paclitaxel + carboplatin + atezolizumab (PD-1 checkpoint inhibitor).

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