Discussion
In this retrospective study, we have evaluated the efficacy and the
safety of the PD-1 inhibitor on locally advanced and advanced NSCLC
patients with chronic viral infection. Results show that the PD-1
inhibitor-based therapy, especially combined with chemotherapy and
bevacizumab, had moderate efficacy on this population. Notably, the
incidence of elevated hepatic transaminase was higher in them than those
without chronic viral infection and other toxicity profile was
acceptable.
In recent past, immunotherapy, especially PD-1/PD-L1 immune checkpoint
inhibitors, has brought new hope for lung cancer patients by activating
the autoimmune system to achieve the effect of killing tumors.
Successful anti-PD-1 / PD-L1 immunotherapy requires an adequate number
of specific T cells in the tumor microenvironment. Similar to the tumor
microenvironment, the chronic viral infection is a strong
immunosuppression environment, leading to specific T cells exhausting4, in theory, it may influence the effect of ICI which
has reversed the role of T cell failure at the same time and undermine
the balance between the host immune system and virus control that has
caused the risk of liver damage. In China the incidence of hepatitis B
is higher. At present, the hepatitis B surface antigen carrying rate
among people aged 1-59 is 7.2%. There are about 93 million chronic HBV
infected people in China, among which more than 20 million active
hepatitis B patients require proper treatment. The efficacy and safety
of immunotherapy for these patients need to be clarified, but existing
clinical trials tend to exclude patients with co-viral infection5.Thus there is not any consensus yet and appropriate
strategy of ICIs in this population needs in depth assessment.
In the existing published articles about safety and efficacy of ICIs in
patients with chronic viral infection and advanced-stage cancer, the
types of cancer involved are not comprehensive, with liver cancer and
melanoma accounting for the majority and NSCLC accounting for less than
five percent 6. In one retrospective study of PD-1
inhibitors for NSCLC with special issues involving 32 HBV-infected
patients, four of nine patients experienced severe AST/ALT elevation
(grade 3 or higher) were HBV patients. And three patients developed
viral reactivations or flares, despite receiving anti-HBV therapy prior
to the immunotherapy. In our study, the incidence of elevated ALT/AST
and increased virus-load was lower than in that study. Differences in
ECOG performance status, prior lines of therapy, and agents combined
with PD-1 antibody of the patients may contribute to the differences
between the two studies7. Given the unavailability of
such information and the limited number of patients in that study, the
results of the two studies were not comparable.
Among 78 patients included in the study, the objective response rate
(ORR) was 24.36% (19/78), and the disease control rate (DCR) was
69.23% (54/78). Comparing the phase III clinical trial Keynote-042 in
the Chinese subgroup study8, the exclusion criteria of
which included patients with a history of infectious diseases, the
overall objective response rate of the immunotherapy group was similar
to the results of this study (24.36% vs. 32.80%) (P=0.250), indicating
that the history of infectious diseases does not affect the short-term
efficacy. In terms of long-term efficacy, the median progression-free
survival (PFS) reached 6.49 months (95% CI :3.71-9.27). Among them, the
first-line treatment shows better efficacy than the second-line and
later treatment (7.67 months vs. 5.57 months, P = 0.129). Previous
studies have proved that the median progression-free survival of
advanced
NSCLC who received pembrolizumab as the first-line immunotherapy was
about 8 months9,10, which is similar to our study, and
that of advanced NSCLC who received nivolumab as the second-line
immunotherapy was about 3 months11,12. In our study,
the median PFS of second- and later-line treatment group seems improved
than the previous studies. This phenomenon may be because the patients’
constitutions are different. In our study, 11.5% of patients were
clinically diagnosed with stage IIIB lung cancer, which may have
improved the results.
In our group analysis, the short-term efficacy of
patients
in
the
first-line treatment group was significantly better than that in the
second-and multi-line treatment groups (48.00% vs. 13.20%)
(P<0.05). The reason may be that patients in the first-line
treatment group have not received other treatments, and there are more
specific T cells in the tumor microenvironment than in second-line and
multi-line patients, which promote the immune system to recover to a
greater extent. The ECOG score of group 0 and group 1 was significantly
higher than that of group 2 (88.23% vs.74.00% vs.18.18%)
(P<0.05), indicating that patients with better physical
conditions are more likely to benefit. The ECOG score of group 2 has
poor efficacy, but no deaths related to adverse reactions of
immunotherapy occurred, and the safety was fair. The 10 patients in the
combined radiotherapy group were all in stable condition, which was
better than the non-radiotherapy group, and the PFS was also
significantly longer than the patients without combined radiotherapy
(14.07 vs.4.62, P=0.027). Because local radiotherapy has a synergistic
effect with immunotherapy by enhancing the uptake of antigen by APC,
promoting DC activation and migration, and tumor-associated antigen
cross-presentation13.
We divided patients into four groups in accordance with the different
agents that were used to combine with the PD-1 inhibitor, drawing the
conclusion that patients who received the PD-1 inhibitor in combination
with the chemotherapy and the bevacizumab therapy obtained the longest
PFS (PD-1 antibody alone vs. PD-1 antibody combined with the
chemotherapy vs. PD-1 antibody combined with the bevacizumab vs. PD-1
antibody combined with the chemotherapy and the bevacizumab groups: 1.44
vs.5.67 vs.1.67 vs.14.13, P=0.002), which is consistent with previous
research.
The incidence of adverse events of any group among 78 patients was
73.07% (57/78), including 7 cases of grade 4 adverse reactions, 3 cases
of bone marrow suppression, 2 cases of pneumonia, 1 case of superior
vena cava obstruction, and 1 case of ketoacidosis. 3 patients who died
due to respiratory failure after receiving immunotherapy for 2 months
were considered to be affected by rapid tumor progression. The incidence
of leukopenia in any grade of adverse reactions was the highest
(57.69%), followed by anemia (25.64%), hepatic transaminase elevating
(24.36%) and fatigue (21.79%). There is no big difference between the
adverse reaction spectrum and the incidence of adverse reactions in
patients with infectious diseases and those of patients without
infectious diseases, but it is worth observing that the proportion of
hepatic transaminase elevating was increased. In the clinical phase III
trials of Keynote001, the proportion of alanine aminotransferase (ALT)
elevating and aspartate aminotransferase (AST) elevating were
respectively 2.2% and 3.0% in the treatment of
pembrolizumab.14 Compared with patients without a
history of infectious diseases, the patients in this study displayed a
higher incidence of hepatotoxicity. Hepatic transaminase increased in
26.7% (16/60) of hepatitis B patients, and remained unchanged in 63.3%
(38/60) patients, as is shown in Table 4. Notably, 5% of hepatitis B
patients showed a decrease in hepatic transaminase. Of the 60 patients
with hepatitis B, viral load remained unchanged in 53, viral load
increased in 2, and viral load decreased in 5. All five patients with
reduced viral load received antiviral therapy. Of the 14 patients who
did not receive antiviral therapy, 3 patients had grade 3 or 4 adverse
events, but in all three patients, the adverse events were reversed with
steroids and ICIs were not discontinued, so the side effects were
considered acceptable. In summary, there was no significant increase in
the incidence of these adverse events in patients with a history of
infectious diseases. Considering the retrospective nature of our study
and small sample size, data from phase IV studies with relaxed inclusion
criteria or from further prospective series are needed to shed more
light on the safety and efficacy of ICIs in this challenging population.
In this retrospective analysis, the efficacy of PD-1/PD-L1 immune
checkpoint inhibitors on locally advanced and advanced NSCLC patients
with a history of infectious diseases was acceptable, safe, and the
clinical outcome was not affected by the history of infectious diseases.
Such patients can benefit from immunotherapy. However, considering that
the incidence of hepatic transaminase elevating has increased, we
recommend close monitoring for such patients in consultation with a
hepatologist and to treat those with active viral hepatitis with
antiviral therapy prior to the immunotherapy.