September 16, 2022
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
If you have stage four non-small cell lung cancer (NSCLC) there is a hopeful new treatment option that shows increased survival rates in patients. New trial results show that a short-course of the immunotherapy drug tremelimumab combined with the drug Imfinzi (also knowns as durvalumab) plus traditional chemotherapy, increased the survival of some patients, as compared to chemotherapy alone, particularly for a subset of patients who have historically fared extremely poorly just with traditional chemo. These results are welcome yet unsurprising, as immunotherapy and chemotherapy combinations have time and again made news for the renewed hope that they offer cancer patients.
The two drugs, tremelimumab and durvalumab, used in the combination arm of the trial, known as Poseidon Phase III, belong to a rapidly evolving class of immunotherapy drugs. These drugs recruit the patient’s own immune system in the fight against their cancer.
“The results provide another treatment approach that may be useful for patients with non small cell lung cancer,” Dr. Salman Punekar, an oncologist at NYU Langone, tells SurivorNet. “The exploratory analysis suggests that certain mutations may retain vulnerability to immunotherapy and chemotherapy combinations.”
Who Does This Drug Target?
Lung cancer is largely split into non small-cell and small-cell lung cancers, with the former being much more common. A diagnosis of is often devastating for the patients, especially since most of them are diagnosed after their cancer has spread outside of the lungs, a stage termed metastatic. This unfortunately means that physicians must forego curative treatments. They must instead focus on improving the quality of life and prolonging the survival of these patients.
Frequently, these patients carry genetic mutations that render them unresponsive to even some of the most cutting-edge drugs and treatments. The treatment cocktail used in the trial, known as Poseidon Phase III, consisting of the two immunotherapy drugs and traditional chemotherapy, holds the promise of improved outcomes for carriers of such mutations, according to an updated exploratory analysis of the trial. The results of this trial were originally presented in late 2021, according to the pharmaceutical company AstraZeneca which conducted the study and manufactures Infimzi.
These results are very much in line with the current scientific literature which shows that combining immunotherapy with traditional therapies has lead to the development of new ways of managing previously notoriously difficult to treat cancers. Dr. Jim Allison, Chair of the Department of Immunology at MD Anderson Cancer Center and the winner of the 2018 Nobel Prize for Physiology or Medicine, previously told SurvivorNet that “I think that the most powerful combinations coming up are based on combining immune blockers or enhancers but also drugs that can directly kill tumor cells to really have a double whammy. And they can be used perhaps even more safely than what we’re doing now and get better responses.”
“Poseidon was a Phase III trial of Imfinzi plus platinum-based chemotherapy … compared to chemotherapy alone in the first-line treatment of 1,013 patients with metastatic non small cell lung cancer,” Shubh Goel, head of immune-oncology and GI tumors at AstraZeneca, told SurvivorNet. A phase III trial is one of the highest levels of evidence used to judge the efficacy of a treatment, prior to its formal approval by the FDA for use within the community.
What distinguishes this study from other similar studies is the inclusion of patients with a wide range of tumor characteristics, including squamous cell and non-squamous cell cancers, and various combinations of known mutations of their cancers (such as those within the KRAS, STK11, and KEAP1 genes).
The KRAS gene mutation is one of the most common mutations within non small cell lung cancer tumors. This mutation by itself is targetable by immunotherapies. However, when certain other mutations are present in the tumors, there are still poor outcomes for patients.
The exploratory analysis of this trial reported after four years of follow-up indicates that the Poseidon treatment combination improves overall survival (OS) and progression free survival (PFS) across all tumor characteristics. The National Institutes of Health defines OS as the length of time patients are alive after their initial diagnosis of cancer, whilst the PFS represents that a patient is alive without a worsening of their disease.
The tremelimumab, durvalumab, and chemotherapy combination improved overall by 50 percent when compared to chemotherapy alone. More specifically, a near double number of patients, 25 percent vs. 13.6 percent, who received the combination treatment were alive at three years compared to those who received chemotherapy alone. These benefits were most notable in patients with a non-squamous histology, and those carrying certain mutations (in this case, within the STK11, KEAP1 and KRAS genes). Interestingly, this held true even for patients who are classified as PD-L1 negative, which is the main target of Imfinzi.
How Do the Drugs Work?
Shubh Goel further tells SurvivorNet that “Imfinzi is a human monoclonal antibody and works by binding to the PD-L1 protein and blocking the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.”
PD-1, PD-L1, and CD80 are proteins that can help cancer cells evade destruction by a patient’s native immune system. More specifically, PD-1 and CD80 are proteins expressed on several immune cells. These proteins can interact with PD-L1, a conjugate protein expressed by tumor cells, essentially rendering tumors invisible to and safe from the immune system. Had this interaction been prevented, the errant tumors cell could have been eliminated by the immune system. Imfinzi accomplishes just that, by binding to PD-L1 and preventing it from interacting with PD-1 and CD80 proteins.
Tremelimumab acts in a similar fashion but targets a different set of proteins. It binds to CTLA-4, a protein expressed on some immune cells. This prevents CTLA-4 from interacting with CD80/86 proteins, which are proteins present on antigen presenting cells, a specific kind of mediator immune cell, which primes the system to attack tumors that express the antigens. The conjugation is thwarted by tremelimumab, which enhances the immune system’s ability to eliminate cancer cells.
The Poseidon Phase III trial combined a short- course of tremelimumab with Imfinzi along with traditional chemotherapy, amalgamating the anti-tumor effects of these individual therapies, which translated into an improvement in meaningful patient outcomes, according to the trial.
Immunotherapies are not without their toxicities. It should be noted that the combination of tremelimumab, Imfinzi, and chemotherapy was very well tolerated.
“Side effects of immunotherapy, called immune related adverse events, often mimic autoimmune conditions. These are medicated by inflammation of different areas of the body. The colon, thyroid, lungs, and skin are commonly affected,” said Dr. Punekar.
However, the trial resulted in 27.6 percent of patients experiencing some adverse effects as compared to 17.7 percent of patients receiving chemotherapy alone, although the overall safety profiles for both were similar.
The most common adverse effects from the combination treatment include immune-mediated reactions, such as an inflammation of the lungs, gastrointestinal tract, liver, kidneys, or the skin. Inflammation of other organs, such the cardiovascular system, can occur but are far less common (less than one percent of patients). Adverse events, attributed to the treatments, which resulted in death occurred in 3.3 percent of patients receiving the combination treatment and 2.4 percent of the patients receiving chemotherapy alone.
Looking to the Future
Currently, Imfinzi is approved for use in non-metastatic lung cancers following the traditional chemotherapy and radiation treatments. The effective double immunotherapy and chemotherapy combination employed by the Poseidon trial is not yet approved by the FDA for routine use within the community. Presently, metastatic non small cell lung cancer patients cannot avail this treatment option through their oncologists. However, because of the promising results of this study, it will not be too long before a serious consideration for this treatment combination becomes a routine part of discussions between oncologist and their patients.
Along with an exploration of the effectiveness of this treatment, such discussions should weigh the risk of side effects, especially in patients who may have compromised lung, gastrointestinal, kidney, or liver functions prior to starting this therapy.