The tantalizing idea of harnessing the immune system to fight cancer has fascinated researchers and clinicians equally for many years. The belief that the body possesses natural defenses to combat cancer existed for a long time, with multiple anecdotal reports of tumors miraculously shrinking, either spontaneously or after an infectious episode.
The link between the immune system and cancer has been recognized for over a century and was first highlighted by Rudolph Virchow more than 150 years ago.1
The first FDA approval of a modern immunotherapy drug was in March 2011, when ipilimumab (Yervoy), a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen 4 or CTLA-4 was first approved for late stage malignant melanoma. Since then, immunotherapy rapidly evolved and is now considered to be the “fifth pillar” of cancer therapy, joining the ranks of surgery, cytotoxic chemotherapy, radiation and targeted therapy.
The most commonly used immunotherapy in lung cancer is a category of monoclonal antibodies including programed death (PD) immune checkpoint inhibitors (ICI) such as nivolumab (Opdivo) or pembrolizumab (Keytruda) or programed death ligand (PDL1) inhibitors such as atezolizumab (Tecentriq) and durvalumab (Imfinzi).
The ICIs are not directly cytotoxic. Instead of killing the cancer cells, the ICI enables a patient’s own immune system, specifically the T cells, to identify and kill the cancer cells.
The T cells protect the body from cancer by killing certain cancer cells. But cancer cells evolve proteins to protect themselves from T cells. ICIs block those protective proteins. Once the proteins are blocked, the T cells can recognize and kill the cancer cells.
By the Numbers
In oncology, we often say no two cancers are the same and no two patients are the same. There are two main categories of lung cancer: small cell and non small cell (NSCLC). The small cell is considered to unfortunately have a poorer prognosis, due to disease biology.
Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women (excluding skin cancer), secondary to prostate cancer, and breast cancer in men and women, respectively.
The American Cancer Society’s estimates for lung cancer in the United States for 2020 are that there will be approximately 228,820 new cases of lung cancer (116,300 in men and 112,520 in women) and approximately 135,720 deaths from lung cancer (72,500 in men and 63,220 in women). Lung cancer is by far the leading cause of cancer death among both men and women, making up almost 25% of all cancer deaths. Each year, more people die of lung cancer than of colon, breast and prostate cancers combined. On the upside, however, the number of deaths from lung cancer is decreasing due to fewer people smoking and advances in early detection and treatment.
Stages Recommended for Immunotherapy
The FDA has currently approved immunotherapy for stage III and IV NSCLC and for stage IV small cell lung cancer. Currently, there are clinical trials with ICI that are enrolling patients with earlier stages of lung cancer.
Although they have produced dramatic results in the treatment of lung cancer, immunotherapy drugs alone are not curative for lung cancer. Many times ICI are used in combination with chemotherapy and/or radiation therapy. All ICI drugs indicated for lung cancer are administered as a 30-60 minute infusion intravenously at 2-4 weeks intervals (depending on the drug).
For stage III NSCLC patients with unresectable disease, the treatment traditionally recommended is concurrent chemoradiation therapy (CCRT). Despite aggressive therapy, the majority of patients will have a recurrence within the first 12 months. The PACIFIC clinical trial found that adding an immunotherapy drug, durvalumab, to the CCRT (“maintenance therapy”) leads to a longer progression-free survival (PFS) as well increased overall survival (OS). In this trial, the OS increased to over 38.4 (median OS not reached) for patients receiving durvalumab versus 29.1 months (95% CI, 22.1–35.1) with placebo.
For stage IV lung cancer, the use of immunotherapy has profoundly changed the way we treat NSCLC. Of note, not all patients are responding to immunotherapy; only approximately 30% of patients will respond to single-agent immunotherapy.
The prediction of response is guided by certain markers. The most used marker is PLD1 tumor proportion score (TPS) expression. Pembrolizumab is the only drug currently approved as monotherapy, first line, for the treatment of patients with NSCLC with a PD-L1 of at least 1% but generally recommended only for those with a TPS of at least 50% (approximately 30% of the first-line population).
In the Keynote 024 clinical trial, pembrolizumab was compared with chemotherapy as first-line treatment for patients with a PDL1 >50%. Pembrolizumab significantly prolonged OS at the first and subsequent analysis. Median follow-up of 25.2 showed a median OS: 30.0 vs. 14.2 months (HR, 0.63; 95% CI, 0.47-0.86; P = .002) in favor of pembrolizumab.
A series of clinical trials compared chemotherapy plus immunotherapy vs. chemotherapy alone in various lines of treatment of stage IV lung cancer: KEYNOTE-189 and -407 (pembrolizumab), and IMpower130, 131 and 132 (atezolizumab) showed increased PFS and OS in favor of immunotherapy.
Side Effects
Although generally IT is better tolerated than chemotherapy, there are several immune-related adverse events (irAEs) described. When the immune system is stimulated, sometimes the T lymphocytes overreach and start attacking the normal tissues, hence the side effects mimic autoimmune disease such as: thyroiditis, hepatitis, colitis, pneumonitis, skin rash (most commonly), but virtually any organ can be affected. Most irAEs develop within the first 12 to 24 weeks of treatment, with skin rashes occurring first. Adverse effects are described in approximately 30% of the patients treated, but they are usually mild, grade 1-2. However, up to 4% of patients treated in the study died as a result of an irAEs.
Treatment of irAEs is first discontinuing the immunotherapy, for more severe symptoms adding high dose steroids 1-2 mg/m2 /day with a long course of taper (3-6 months). For patients not responding to steroids, anti-tumor necrosis factor (anti-TNF) drugs such as inflixamab (Remicade) have been used with good results.
The addition of immunotherapy in the management of lung cancer has changed not only the way we treat lung cancer, but also the way we think about the prognosis of lung cancer patients. Advanced lung cancer was once a death sentence, but now we are starting to think about it as a chronic disease and, in certain cases, a curable disease.
Immunotherapy is arguably the biggest leap made in the fight against cancer over the last 15 years. As the field of immuno-oncology evolves, we see more and more patients with different cancer types benefiting from this modality.
Today, there is a role for immunotherapy virtually in every cancer therapy, including breast, colon, liver, head and neck, certain blood cancers and more. As a recognition of the impact this new treatment modality had, in 2018 the Nobel Prize for Medicine or Physiology was awarded to James P. Allison of the University of Texas MD Anderson Cancer Center and Tasuku Honjo of Kyoto University for their discovery of cancer therapy by inhibition of negative immune regulation.
What once was an idea in a lab turned out to be a powerful tool for cancer treatment. And I believe this is just the beginning of a new era in the fight against cancer.
Ioana Bonta, MD
Dr. Bonta is a board-certified physician in medical oncology specializing in systemic therapies such as immunotherapy, targeted therapy, chemotherapy and combined modalities. Dr. Bonta is a staff oncologist with Georgia Cancer Specialists affiliated with Northside Hospital Cancer Institute and is an adjunct clinical assistant professor at Morehouse School of Medicine. She holds two patents in oncology-related topics and is a member of the American Society of Clinical Oncologists and the International Association for the Study of Lung Cancer.
References
1.Big opportunities for small molecules in immuno-oncology.
Adams JL et all Nat Rev Drug Discov. 2015 Sep; 14(9):603-22.
2. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html
Last accessed March 30, 2020
3. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer, Antonia S et all, NEJM, Nov 2017
4. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC, Antonia, S, NEJM 2018
