What Is a Durable Response With Cancer Treatment?

The term durable response with cancer treatment is now used quite often, but can be very confusing to people living with cancer. There is not a standardized definition, but it usually refers to a response to treatment that is much longer than expected for a metastatic (stage 4) solid tumor (such as lung cancer, breast cancer, etc.) While durable responses have rarely been seen with other treatments, the use of immunotherapy drugs to treat cancer has led to a much greater number of these responses.

Durable Response: Definition and Meaning

There is not a generally accepted definition of durable response, though the term has begun to be used widely in oncology. Most often it refers to a prolonged response to therapy for a metastatic (stage 4) solid tumor that is beyond the type of response ordinarily seen with any treatment. Some physicians have arbitrarily defined this period of time to be at least one year.

Not everyone who is treated with immunotherapy drugs will obtain a durable response, which still remains the exception rather than the rule. Another term is exceptional responders, which refers to people who respond to treatment in a way that goes beyond what oncologists would have predicted based on past experience with a cancer.

For the purposes of research studies, different working definitions have been adopted, though there may be people who are considered to have a durable response even though they do not meet these descriptions. In one study, for example, researchers defined durable response as having a progression-free survival that was at least three times that of the median progression-free survival of all patients treated with the same drug in the same clinical trial for a period of six months or more.

When Is the Term Durable Response Used?

Your oncologist may use the term durable response when talking about how you are doing on your immunotherapy drugs. The term is also frequently used as an endpoint in clinical trials. Other similar terms that you may see include duration of clinical benefit (how long a drug appears to keep a cancer at bay) or drug durability (how likely a drug may be to result in a durable response).

Durable Response vs. Remission

Many people wonder what the difference is between a durable response and remission. Remission can be either complete (no evidence of tumor) or partial (a 30% or greater decrease in size of a tumor). The cancer does not have to be completely gone to qualify as a durable response.

Durable Response vs. Cure

A question that can't yet be answered at this time is whether a durable response, at least in some cases, may represent a cure.

While early-stage cancers may be treated and never recur (for example, with surgery and chemotherapy), metastatic (stage 4) solid tumors such as lung cancer, melanoma, breast cancer, and colon cancer would almost always be expected to progress (and lead to death) without treatment. The fact that some metastatic solid tumors have remained at bay after treatment with immunotherapy (even after treatment is stopped) suggests that at least in some cases the tumors may never return (i.e. be cured). Yet it is simply too soon to know how long a prolonged durable response will last.

The longest-term data currently available is with the use of Yervoy for melanoma. In one study, the overall survival curve (the number of people surviving after treatment) reached a plateau of 21% at three years which persisted with follow-up up to 10 years. Roughly one in five people achieved a durable response for that long.

In another study that looked at three-year survival among people with melanoma treated with Keytruda (pembrolizumab), a very low risk of relapse after complete remission on the drug led researchers to conclude "Patients with metastatic melanoma can have a durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately two years from discontinuation provides hope for a cure for some patients."

Mechanism

The immune system is programmed to fight cancer. The problem arises when cancer cells either secrete substances or alter normal cells in their surroundings such that they can "hide." Checkpoint inhibitors work, simplistically, by taking the "mask" off of cancer cells so that the immune system can recognize and then attack them. Since the immune system can (albeit in the minority of patients) better recognize cancer cells after treatment, it makes sense that it would continue to work even after the medications are discontinued. In fact, the rare occurrence of the spontaneous remission of cancer is thought to work in this way.

There are some problems in this theory that may lead to a recurrence of a cancer even after a durable response occurs. Cancer cells are continually developing new mutations, including resistance mutations that allow them to escape cancer treatments or detection by the immune system. It's also possible that the immune system's response may simply be insufficient (T cell exhaustion) to continue to fight off cancer cells.

Unique Terms Associated With Immunotherapy

Durable responses are not the only type of phenomena that are seen with immunotherapy drugs much more than other treatments (or in some cases, only with immunotherapy).

Checkpoint inhibitors work by essentially allowing the immune system to see cancer cells, but this process (learning to recognize, gathering an "army" of cells, and then attacking a cancer) takes time. Unlike the rapid decrease in the size of a tumor sometimes seen with chemotherapy, immunotherapy drugs may not appear to be working for some time.

Pseudoprogression

Tumors may continue to grow for some time, or at least, in some cases, appear to grow and progress. The concept of pseudoprogression with immunotherapy (the appearance that a cancer has grown on imaging scans while it is actually responding) can be very confusing to people receiving these treatments, and is the reason they are often continued even if a prompt response is not seen.

When looked at under the microscope, these tumors may be surrounded by immune cells, and in some cases, even though a tumor looked larger on a computed tomography (CT) scan, most of what was seen was the immune cells and not tumor.

Hyperprogression

In contrast to normal progression (the progression of a cancer that's expected if it does not respond to a treatment), hyperprogression with immunotherapy may uncommonly occur.

Continued Response After Treatment Is Stopped

Most often, if medications such as targeted therapies are stopped, a cancer begins to grow again, even if it appeared to be in complete remission. In contrast, it's now not uncommon for an advanced solid tumor to stay in remission after checkpoint inhibitors are stopped. When these drugs can be safely stopped, however, is uncertain. (Other types of treatments for metastatic solid tumors are usually continued until a tumor progresses.)

Dissociated Responses

Yet another type of response seen with immunotherapy drugs (but much less commonly with other treatments) is the phenomena of dissociated responses. This means that some areas of a tumor (or metastases) may decrease in size with the treatment whereas other areas may continue to grow. This has been confusing to many people as sometimes local treatments (such as radiation) are used to control those areas that continue to grow while the immunotherapy drug is continued.

Cancer Types and Treatments and Durable Responses

Durable responses to treatment of metastatic solid tumors are not unique to immunotherapy drugs (they are rarely seen with chemotherapy drugs, etc.), but are much more common with these drugs. For example, a 2019 study looking at people with lung cancer found that durable responses were more frequent in people treated with checkpoint inhibitors, but also occurred in people treated with some other classes of drugs (eg. chemotherapy drugs, targeted therapies).

It's important to note that checkpoint inhibitors are only one type of immunotherapy, a class of treatments that also includes oncolytic viruses, CAR T-cell therapy, and much more.

Since there are so many different cancer medications available now, it's helpful to list the drugs that are considered checkpoint inhibitors. These are broken down into three different categories.

PD-1 Inhibitors (programmed cell death protein 1)

• Opdivo (nivolumab)
• Keytruda (pembrolizumab)
• Libtayo (cemiplimab)

PD-L1 Inhibitors (programmed death ligand 1)

• Tecentriq (atezolizumab)
• Bavencio (avelumab)
• Imfinzi (durvalumab)

CTLA-4 (cytotoxic T lymphocyte associated protein 4)

• Yervoy (ipilimumab)

Cancer Types and Durable Responses

Durable responses on immunotherapy have now been seen with a number of different types of metastatic cancer, including:

• Melanoma
• Non-small cell lung cancer
• Kidney cancer (renal cell carcinoma)
• Head and neck cancer
• Bladder cancer
• Hodgkin lymphoma
• Merkel cell carcinoma
• Triple-negative breast cancer
• Glioma
• Refractory cervical cancer
• Colorectal cancer (with microsatellite instability)
• Gastroesophageal cancer

Predictors of a Durable Response

Since achieving a durable response is the closest thing we currently have to a "cure" for most advanced cancers, researchers have been looking for ways to determine who is likely to have a durable response when treated with immunotherapy. Unfortunately, there is not a single test or set of factors that can reliably predict for certain who will respond or go on to have a durable response on these drugs. There are, however, some factors that suggest these drugs will be more effective.

Mutational Burden

The term "mutation burden" refers to the number of mutations in a cancer. Most cancers do not have a single mutation, but may instead may have up to hundreds of mutations that occur in the process of a cell becoming cancerous, or during the subsequent rapid growth of the cell.

A higher mutation burden is associated with a response to immunotherapy drugs, but there is much variation. Some tumors with a low mutation burden may respond well, whereas some with a high mutation burden may not respond at all. That a high mutation burden would correlate with a response (and the potential for a durable response) makes sense. In theory, more mutations in a tumor should make it appear "less like self" and therefore easier to "see" by the immune system.

With lung cancer, tumor mutation burden tends to be much higher in people who have smoked than never smokers, and in fact, durable responses to Opdivo (defined as being alive five years after Opdivo was started for metastatic lung cancer) were much more common in current or former smokers (88%) than never smokers (6%).

PD-L1 Expression

PD-L1 expression is measured in some cancers on a tumor to predict whether immunotherapy will be effective. People who have tumors that expressed PD-L1 in 1% or more of tumor cells were more likely to have a durable response (70%) than those who had PD-L1 expression less than 1%.

Despite PD-L1 expression correlating with response, some people with very low PD-L1 expression have responded remarkably well to these drugs, and choosing who to treat based on PD-L1 expression would exclude some people who might have an excellent response (that would likely be impossible with any other currently available treatment).

Response vs. Progression on Immunotherapy Drugs

It's not surprising that people who respond to immunotherapy drugs (their tumor begins to shrink or shrinks completely) are more likely to have a durable response. People who had at least a partial response to these drugs (a tumor decreased in size by 30% or more) were much more likely to have a durable response (75%) than people whose tumors progressed when treated with these drugs (12%).

When treatment results in a complete remission, the likelihood of a durable response is quite high, at least with melanoma. A study looking at people with metastatic melanoma treated with Yervoy found that 96% of people who had a complete metabolic response at one year (no evidence of the cancer on a positron emission tomography [PET] scan) continued to remain cancer-free after the drug was discontinued.

Under the microscope, cancers that have larger numbers of tumor-infiltrating lymphocytes are a lot more likely to respond to immunotherapy (checkpoint inhibitors).

A Word From Verywell

Being diagnosed with cancer is like learning a new language, and with immunotherapy, much of that is language that oncologists and researchers had not heard of a decade ago. Learning about your cancer, your treatments, and how these therapies work may not only help you feel more in control of your journey, but has sometimes made a difference in outcomes as well.

We've reached a time at which cancer treatments are advancing so rapidly, that oftentimes people living with cancer are more familiar with the treatments and clinical trials available for their specific type and subtype of cancer than community oncologists who treat all types of cancer. Make sure to ask questions and consider getting a second opinion with a physician who specializes in your type of cancer. The fact that you are learning about durable responses indicates you are already doing something that may ease both the emotional and physical upheaval of cancer; being your own advocate.