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Written by | Su Xuhan
The emergence of immune checkpoint inhibitors (ICIs) has greatly changed the treatment and prognosis of patients with various malignancies such as non-small cell lung cancer (NSCLC), small cell lung cancer, and breast cancer.
Due to the complexity of the tumor microenvironment and the heterogeneity of tumors, ICIs can disrupt the body's immune balance while achieving significant efficacy, resulting in a series of immune-related adverse events (irAEs) that can affect multiple organ systems. Despite their promising clinical efficacy, the development of irAEs in clinical treatment has greatly limited the use of ICIs in many cancer patients.
However, in recent years, a number of studies have shown that irAEs, which are feared, are associated with a better prognosis in cancer patients. The medical community has compiled a summary of previous related researches to explore the relationship between irAEs and the efficacy of immunotherapy.
IMpower系列研究:irAEs预示着更长的OS、更高的ORR
JAMA Oncology published the results of a post-hoc exploratory analysis that summarized data from the IMpower130, IMpower132, and IMpower150 trials, all of which were phase III prospective clinical trials evaluating the efficacy and safety of the PD-L1 inhibitor atezolizumab in combination with chemotherapy in patients with advanced NSCLC, to evaluate the relationship between irAEs and atezolizumab efficacy in patients with advanced NSCLC.
- In IMpower130, patients were randomized in a 2:1 ratio to receive atezolizumab + chemotherapy in combination (atezolizumab + carboplatin + nab-paclitaxel) or chemotherapy alone (carboplatin + nab-paclitaxel). At the end of the treatment cycle, the combination group received atezolizumab maintenance therapy, and the chemotherapy group received the best supportive care or pemetrexed maintenance therapy until there was no clinical benefit or disease progression.
- In IMpower132, patients were randomized in a 1:1 ratio to receive atezolizumab + chemotherapy (atezolizumab + carboplatin + pemetrexed + platinum) or chemotherapy alone (pemetrexed + platinum), followed by maintenance therapy (atezolizumab + pemetrexed or pemetrexed alone) until disease progression, unacceptable toxicity, or death.
- In IMpower150, patients were randomly assigned to receive ABCP regimen (atezolizumab + bevacizumab + carboplatin + paclitaxel), ACP regimen (atezolizumab + carboplatin + paclitaxel) and BCP regimen (bevacizumab + carboplatin + paclitaxel) in a 1:1:1 ratio, followed by maintenance therapy with atezolizumab + bevacizumab, atezolizumab and bevacizumab, respectively.
In this study, the data from the above three trials were summarized and divided into atezolizumab and control groups. A total of 2503 patients were included in the demographic and baseline analysis, including 1577 in the atezolizumab group and 926 in the control group. There were 753 and 289 patients in the atezolizumab and control groups who developed irAEs of any grade, respectively. The incidence of grade 3 to 5 irAEs was 11 versus 174 versus 5 percent (45 cases) in both groups, respectively. The most common irAEs in both groups were rash, hepatitis, and hypothyroidism.
The results of the study are as follows:
- The median OS of patients with irAEs was 25.7 months (95% CI 23.9-29.1) compared with 13.0 months (95% CI 11.7-13.9) in patients without irAEs in the atezolizumab group (HR = 0.69, 95% CI 0.60-0.78), with significant differences between groups.
- In the control group, the median OS was 20.2 months (95% CI 18.2-22.8) and 12.8 months (95% CI 12.0-13.9) for patients with and without irAEs (HR=0.82, 0.68-0.99), respectively, with significant differences between groups.
Figure 1 OS ending
- ORRs were 61 versus 37 percent in patients with and without irAEs in atezolizumab compared with 42 versus 34 percent in the control group. The median time to response was 1.7 months for patients with and without irAEs in the atezolizumab group compared with 1.6 versus 1.5 months in the control group.
The more severe the adverse reaction, the better the effect?
Subgroup analysis of atezolizumab groups according to the time node of irAEs (1, 3, 6, 12 months) showed that:
- In all landmark subgroups, patients with grade 1/2 irAEs had a longer median OS than those with grade 3 to 5 irAEs or no irAEs;
- Patients with grade 3 to 5 irAEs in the atezolizumab group had shorter OS than those with grade 1/2 irAEs or no irAEs. In the 12-month analysis of irAEs, patients with grade 3 to 5 irAEs had a longer median OS than those without irAEs.
Figure 2 OS analyzed by time node of irAEs
In summary, patients who developed irAEs demonstrated longer OS and higher ORR than NSCLC patients who did not develop irAEs in the atezolizumab group. Subgroup analyses based on time nodes showed that patients who developed irAEs had longer OS than those who did not, but the atezolizumab group had a higher benefit compared with the control group, regardless of whether the patients had had irAEs.
In this regard, the research group proposed that ICIs-related irAEs may be associated with enhanced anti-tumor immune response, but the association between individual irAEs and atezolizumab efficacy still needs to be further studied.
The KEYNOTE series of studies showed anti-tumor activity in patients with irAEs
KEYNOTE-355 is a randomized, placebo-controlled, double-blind phase III clinical trial comparing the efficacy and safety of the PD-1 inhibitor pembrolizumab + chemotherapy versus placebo + chemotherapy in the first-line treatment of advanced triple-negative breast cancer, and previous studies have shown that pembrolizumab significantly improves PFS in patients with PD-L1 CPS≥10, with a median OS extension of 23.0 months and a 27% reduction in the risk of death [1-2].
At the 2023 European Society for Medical Oncology Breast Cancer Congress (ESMO BC), clinical outcomes in two specific patient categories in the KEYNOTE-355 study were reported:
a) Patients who received pembrolizumab + chemotherapy to achieve a complete response (CR), partial response (PR) or stable disease (SD) lasting ≥ 24 weeks, and the duration of the last chemotherapy was 21 days > than the last dose of pembrolizumab;
b) Patients receiving pembrolizumab + chemotherapy with ≥ 1 irAEs (list of preferred terms compiled according to CTCAE v4.0).
- Results showed that a total of 317 patients in the pembrolizumab + chemotherapy arm (n=566) achieved CR, PR, or SD for ≥ 24 weeks. In these patients, regardless of PD-L1 CPS ≥1/ PD-L1 CPS ≥10, the efficacy of patients who discontinued chemotherapy early was comparable to that of patients as a whole, i.e., early discontinuation of chemotherapy did not adversely affect the clinical benefit of pembrolizumab, and the clinical benefit was not related to PD-L1 CPS levels.
- The median PFS was 7.5 months in the overall population and 9.7 months in patients with irAEs in all patients treated with pembrolizumab, and 17.2 months in the overall population compared with 23.9 months in patients with irAEs.
Fig.4 Survival outcomes of patients with irAEs
That is, evidence of antitumor activity in patients with irAEs, both in overall analysis and in subgroup analyses classified by PD-L1 CPS.
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Adverse effects of immunotherapy are like a double-edged sword: on the one hand, irAEs can be life-threatening; On the other hand, irAEs in turn imply an active immune status. Therefore, how to manage irAEs is a challenge for physicians.
Immunotherapy is complex, uncertain, and risky, and more evidence-based medical evidence is needed to guide clinical practice. At present, a large number of ICIs are being carried out in preclinical and clinical studies to explore biomarkers that can effectively predict the efficacy and toxicity of ICIs, provide real-time monitoring for precise guidance of immunotherapy, and improve the clinical benefit of patients.
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Bibliography:
[1] Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020; 396(10265):1817-1828.
[2] Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022; 387(3):217-226.
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