Discussion
Immunotherapy has become an important treatment in advanced and
metastatic gastric adenocarcinoma. We present a case of an 89 year old
woman who underwent treatment with pembrolizumab for metastatic gastric
adenocarcinoma and discontinued the therapy after only three doses due
to severe fatigue and poor appetite. While there was no laboratory
evidence that the fatigue and appetite suppression she experienced were
related to the immunotherapy, her fatigue and constitutional symptoms
were profound, required hospitalization, and did likely represent an
immune-related adverse event. Despite a short course of treatment, her
disease continued to improve off of therapy and at the time of last
follow-up, nine months after the last dose of immunotherapy, her only
remaining disease was one metastasis in the liver.
Durable responses such as this have been documented in other forms of
malignancy where immunotherapy is more commonly used, such as melanoma.
However, melanoma is known to be a particularly immunogenic tumor,
partially due to its high mutational burden (6). It is also understood
that durable responses happen more frequently with treatment with
immunotherapy than other cancer-directed therapies and that durable
responses occur more frequently with PD-1 or PD-L1 inhibitors than with
CTLA-4 inhibitors (10). As immunotherapy becomes more frequently used in
other tumor types such as gastric adenocarcinoma, which are less
immunogenic, it will be important to attempt to understand which
patients may sustain these durable responses.
There is currently no standard definition of durable response and it is
not understood why some patients develop a durable response while others
do not. Check-point inhibitor therapy works by blocking either PD-1,
PD-L1, or CTLA-4 which are proteins that when activated, prevent T-cells
from killing tumor cells (4). When one or more of these proteins are
blocked, a T-cell mediated immune response is stimulated to kill cancer
cells. Once that response to tumor cells is stimulated, it probably does
not require continued administration of the drug to maintain that
response but not enough is understood about the immune response that
develops.
One key to understanding this may be examination of tumor-infiltrating
lymphocytes (TILs) (12). The presence of these cells in the tumor has
been correlated with a positive response in a number of malignancies.
TILs with a high PD-1 expression have been shown to be predictive of a
response to checkpoint inhibitor therapy in patients with non-small cell
lung cancer (13). Perhaps the presence and amount of TILs in the tumor
could help predict which patients may have a durable response.
Patients who develop irAEs are known to be more likely to have durable
responses to immunotherapy. In one study of melanoma patients, 81.2% of
patients who discontinued immunotherapy due to an irAE had a durable
response (3). This was true even in patients who did not have a complete
response, which was previously thought to be uncommon based on
KEYNOTE-001. These patients seem to develop an adaptive memory immune
response that prolongs their response to therapy.
Radiologic response to treatment is another factor that is understood to
be a predictor of durable response in melanoma patients. One study
evaluated 104 patients with melanoma who received immunotherapy (14). 78
patients had a complete metabolic response (CMR) on PET scan at 1 year
after the initiation of therapy. Of these patients, 78% then
discontinued therapy. After a median follow-up time after
discontinuation of therapy of 14.5 months, 96% of these patients
remained progression free. Obtaining a CMR on PET therefore seems
predictive that patients will have an ongoing response to treatment,
regardless of whether they’re continued on therapy or not.
The number of necessary doses of immunotherapy to continue after a
radiologic response is identified is not well-defined. Most trials
evaluating immunotherapy response, especially in patients with
metastatic disease, have used 2 years of administration of the drug to
mark a “completion” of therapy. This originated from the design of
some of the first checkpoint inhibitor therapy trials in melanoma and
has been utilized in most checkpoint inhibitor trials thereafter (8).
This cut off for therapy completion was used in both the KEYNOTE-059 and
KEYNOTE-062 trials in gastric adenocarcinoma (1, 2). The KEYNOTE-001
trial in melanoma had a protocol amendment that allowed patients who had
a complete response and who had received immunotherapy for 6 months to
discontinue treatment after they had received additional 2 doses of
immunotherapy following the imaging on which they were assessed to have
had a complete response (15). Otherwise, there has been a somewhat
pervasive use of the seemingly arbitrary cut off of 2 years of treatment
in trials. This has influenced the way most oncologists practice,
especially as there is limited data to suggest a different approach.
Trials examining the appropriate duration of immunotherapy are slowly
becoming more common. An exploratory analysis of the Checkmate 153
trial, which evaluated the use of nivolumab in patients with advanced or
metastatic non-small cell lung cancer, was performed to examine whether
using a fixed duration of 1 year of therapy or continuing nivolumab
after 1 year impacted outcomes. The patients were randomly assigned to
the two groups. Both progression free survival and overall survival were
improved with continued therapy (11). This may have been due to the fact
that patient response assessment or any other patient factors were not
used to decide whether or not to continue therapy after 1 year.
The HIMALAYA trial in hepatocellular carcinoma showed that a single
priming dose of tremelimumab (a CTLA-4 inhibitor), given with durvalumab
(a PD-L1 inhibitor), was sufficient to confer ongoing benefit when only
durvalumab was continued (7). There was a 30.7% three year overall
survival with the single dose of tremelimumab plus ongoing durvalumab
versus a 24.7% three year overall survival with durvalumab given alone.
This trial demonstrates that immune surveillance likely persists once it
is triggered, even with a single dose of combination immunotherapy.
There are some trials under way in melanoma to help better determine the
appropriate duration of immunotherapy. These trials are using various
measures of patient response assessments to determine which patients
stop therapy and which patients continue. For example, the Safe Stop
Trial is currently evaluating whether it is safe to discontinue
immunotherapy at the time of complete or even partial response in
patients with melanoma (9).
While trials are ongoing in melanoma, very little research is being
conducted to understand the appropriate duration of therapy in other
malignancies, such as in gastrointestinal malignancies. Cases such as
ours, in which patients discontinue immunotherapy and have durable
responses, need to be continually reported and evaluated. Some patients,
including those with GI malignancies, may only require a short duration
of immunotherapy to derive long-term benefit. This case report indicates
that some patients who experience immune related adverse events
requiring discontinuation of therapy may experience a period of
protracted remission and need not immediately plan for alternative
systemic therapy options.
Identifying the appropriate length of treatment in these patients will
be an important aspect in ongoing efforts to improve value-based care
for patients in oncology. Immunotherapy is often much more expensive
than chemotherapy. Pembrolizumab is about $10,000 per dose and
nivolumab is about $7,000 per dose (16,17). Patients often receive
months or years of these therapies after they’ve had a documented
remission. If patients who may have a protracted complete response to
immunotherapy are identified early, hundreds of thousands of dollars per
patient could likely be saved. It would also reduce the burden on the
healthcare system as these patients would not need appointments for
infusions or frequent labs and follow-up visits. It is imperative that
research be pursued to better understand the appropriate length of
immunotherapy treatment for individualized patients.