Rechallenge of immune checkpoint inhibitor after local therapy for immune checkpoint inhibitor-resistant non-small cell lung cancer

Introduction

In 2021, the long-term efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) in second-line treatment was demonstrated (1). Since then, the utility of ICI monotherapy, as well as combination therapies involving chemotherapy or other ICIs, has been shown in first-line treatments (2-5). As a result, long-term survival has become attainable for NSCLC patients using ICIs. However, the proportion of patients achieving long-term survival has remained relatively low compared to patients with melanoma (6). In fact, many NSCLC patients experience early progression (primary resistance) shortly after the initiation of ICI therapy, or relapse after initial response (acquired resistance). Moreover, some patients experience tumor re-growth due to immune-related adverse events, making continued ICI treatment difficult. Therapeutic strategies for patients with ICI resistance are therefore urgently needed. This study investigated the efficacy of ICI rechallenge in NSCLC patients who experienced disease progression after initial treatment with an ICI-containing regimen, focusing on whether local therapy had been administered prior to rechallenge. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-3/rc).

Methods

Patients

We retrospectively reviewed the records of advanced NSCLC patients for whom response was evaluated as “progressive disease (PD)” after administration of an ICI-containing regimen as first-line treatment and rechallenge with an ICI in Funabashi Municipal Medical Center between January 2020 and March 2024. The effectiveness of rechallenge was analyzed based on whether local therapy (including beyond PD with local therapy) was performed prior to rechallenge. Local therapy was selected according to the judgment of the attending physician.

Anonymized clinical data were collected from medical records, including sex, age, smoking status, histological subtype, gene alteration status, programmed death-ligand 1 (PD-L1) expression status, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, liver/brain metastases, and best response to first-line therapy.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the institutional ethics committee at Funabashi Municipal Medical Center (No. 3-26) and the need to obtain individual consent for this analysis was waived based on the retrospective nature of the investigation.

Statistical analysis

The background characteristics of patient were compared using Mann-Whitney U tests, Chi-squared tests, or Fisher’s exact tests. Progression-free survival (PFS) was calculated from the day of ICI therapy rechallenge (or, if used beyond PD, from first administration of ICI after local treatment) until the date of Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression. Overall survival (OS) was measured from the day of ICI therapy rechallenge (or from first administration of ICI after local treatment if used beyond PD) until death, with censoring as of the date of the last visit for patients for whom death could not be confirmed. PFS and OS were compared using Kaplan-Meier methods and log-rank testing, with a significance threshold of P<0.05. The data cutoff date was November 30, 2024. Statistical analysis was performed using SPSS version 29.0 software (IBM, Armonk, NY, USA).

Results

The local therapy group and no-local therapy group comprised 10 patients each. No significant differences in background characteristics were apparent between groups, although the no-local therapy group tended to show a higher number of organs with residual metastases at the time of rechallenge (Table 1). The local therapy performed just prior to rechallenge included (chemo)radiation therapy for the primary lesion in six cases, palliative radiation for metastatic lesions in three cases, and surgery for metastatic lesions in one case. In all cases with ICIs administered after local treatment, monotherapy was used. The median time from local therapy to rechallenge was 1.5 months (Table 2).

Patients with ICI rechallenge after local therapy showed a significantly longer median PFS (9.0 months) compared to patients without local therapy (1.6 months, P=0.02) (Figure 1), particularly in cases where radiation therapy had been applied to the primary lesion just prior to rechallenge (Table 2). On the other hand, no significant difference in OS has been identified between the local treatment group (21.4 months) and no-local treatment group (18.8 months, P=0.12) as of the time of writing (Figure 1). No serious adverse events were observed (Table 3).

Figure 1 Kaplan-Meier curves for PFS (A) and OS (B). OS, overall survival; PFS, progression-free survival.

Discussion

The present findings suggest that ICI rechallenge following local therapy in NSCLC patients who have developed resistance to ICIs may lead to an extension of PFS compared to that in patients who do not receive local therapy.

Regarding expert opinions on ICI rechallenge in cases of ICI resistance, ICI rechallenge may be considered less effective than initial treatment, but not unnecessary (7). However, the optimal timing, selection of appropriate patients, and type of treatment that would be most effective remain insufficiently understood and have yet to be fully clarified.

Recurrent disease after ICI treatment can be classified into oligoprogressive disease and systemic progression. Oligoprogressive disease describes a situation in which a patient experiences disease progression in a limited number of sites after induction therapy has resulted in some degree of response. This phenomenon is thought to be driven by the presence of heterogeneous tumor cells (8).

Niibe proposed the concept of oligo-recurrence before the ICI era, emphasizing that controlling the primary site could allow for the treatment of all metastatic recurrences with local therapy (9).

On the other hand, a study by Xu et al. defined oligoprogression as ≤2 sites and ≤2 lesions showing progression and considered treatment with local therapy as feasible. Systemic progression was defined as ≥3 sites and ≥3 lesions (usually ≥5) showing progression (10).

Oligo-recurrence may require a different treatment strategy compared to systemic recurrence. In cases with ICI treatment continuing beyond PD, OS was similar to that in patients who did not continue ICI, but benefits were observed in cases with a longer duration of first-line treatment, observed shrinkage, or oligoprogressive disease (11). On the other hand, PFS was better in the ICI continuation group, with a median of 8.7 months, compared to 4.1 months in the non-continuation group. In our study, although no significant difference was seen, the local treatment group tended to show more cases of oligoprogressive disease, which may have contributed to the favorable PFS observed.

Kagawa et al. reported that cases of oligoprogressive disease treated with local therapy displayed no significant difference in OS compared to cases in which local therapy was not provided (12). In that study, about half of the patients received ICI rechallenge after local therapy. In addition, all cases had only one site of recurrence, indicating that the prognosis was generally favorable for the study population. The impact of subsequent treatments could thus potentially play a significant role in long-term outcomes.

Wang et al. reported that in 24 cases of oligometastasis with ≤2 sites of progression after achieving complete response (CR)/partial response (PR) with initial ICI treatment, median PFS and OS after treatment with a combination of stereotactic body radiation therapy (SBRT) and ICI were 11 and 34 months, respectively. Among those cases, 70.8% received ICI rechallenge in combination with chemotherapy (13).

Conversely, another study reported that radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2 (14). In that study, since radiotherapy was used as second-line treatment, the ICIs used during first-line treatment may still have been present in the body even in the group that did not receive ICI rechallenge. Strictly differentiating between radiotherapy alone and combination therapy for that study thus seem potentially difficult (15).

In our study, even including cases where CR/PR was not achieved in the initial treatment, patients who underwent ICI rechallenge following local therapy achieved more than 9 months of PFS, with some potentially being close to a cure (Table 2). The efficacy of rechallenging ICI after local therapy on survival has not been demonstrated. However, the observation period is still insufficient. There is a possibility that a difference in survival may be demonstrated at a later period.

In our study, all ICI rechallenge treatments were administered as monotherapy. In most cases, a PD-1 antibody was used with the expectation of its effect on potential metastatic lesions. In cases of oligoprogression, it is hypothesized that rechallenging ICI after local therapy may lead to synergistic effects, such as the abscopal effect.

The abscopal effect was proposed by Mole in 1953 and refers to an immune-mediated response against tumor cells located distant from the radiation site, induced by the generation of neoantigens from the tumor cells damaged by radiation (16). Radiation generates neoantigens by destroying tumor cells. These antigens from damaged tumor cells are taken up by antigen-presenting cells, which then migrate to lymph nodes and promote T-cell-mediated abscopal effects. Subsequently, activated T-cells targeting these tumor-specific antigens are believed to infiltrate both the primary tumor and non-irradiated metastatic lesions (17).

In our study, following ICI rechallenge after irradiation of the primary tumor, we observed cases in which brain metastases that had been recurring became undetectable. This may have been due to the release of numerous cancer antigens from the irradiated primary tumor, which contains heterogeneous cancer cells, leading to the activation of lymphocytes specific to those antigens. This, in turn, would enable the destruction of more cancer cells than during initial treatment. In other words, irradiation of the primary tumor rather than metastatic lesions may result in the release of a broader range of cancer antigens, potentially activating lymphocytes with a greater variety of epitopes. Radiation therapy to the primary tumor is thought to more effectively induce the abscopal effect. In addition, radiation therapy to the primary tumor may also eliminate myeloid-derived suppressor cells, which are believed to contribute to ICI resistance (18).

In our study, although the local therapy group included a higher number of oligoprogressive cases, PFS was significantly extended to 9.0 months compared to 1.6 months in the no-local therapy group. Further, these results were better than the PFS observed with the standard second-line treatment, which comprised a combination of docetaxel and ramucirumab.

Second-line chemotherapy is often administered in cases showing resistance to ICI treatment. In particular, regimens that include anti-angiogenic agents have been shown to result in better response rates and PFS compared to non-ICI treatment regimens (19).

In addition, effective targeted therapies for driver mutations can sometimes result in significant tumor shrinkage. In some cases, this leads to a reduction in the number of metastatic organs, returning the patient to a state of oligometastasis. In such cases, even if resistance to treatment develops, metastasis or progression does not always occur throughout the body, and the number of progressing organs or new lesions may remain limited. In these situations, a treatment strategy that involves local therapy to sites of progression followed by rechallenge of ICI therapy could represent a highly effective treatment option.

In our study, we observed longer PFS with ICI rechallenge, particularly after radiation therapy to the primary tumor. This result is similar to the positive outcomes seen in patients with stage III NSCLC, for whom consolidation therapy with durvalumab was started within 2 weeks after completing radiation therapy (20). Further, within the PACIFIC regimen [a phase III, randomized, double-blind, placebo-controlled, multi-center, international study of durvalumab as sequential therapy in patients with locally advanced, unresectable NSCLC (stage III) who have not progressed following definitive, platinum-based, concurrent chemoradiation therapy], some cases may already have micrometastases at the cellular level, but not detectable on imaging. This suggests that even in stage IV cases, particularly those with oligometastasis, administration of ICI after chemoradiotherapy to the primary tumor could contribute to longer survival compared to ICI monotherapy alone.

The introduction of intensity-modulated radiation therapy (IMRT) could have significant impacts on the addition of local therapy. Although administering ICI close to radiation treatment may increase the risk of immune-related interstitial lung disease, IMRT can substantially reduce the exposure of healthy lung tissue to radiation, thereby minimizing the occurrence of interstitial lung disease while still achieving treatment efficacy. A study has shown that with V20 <20%, the incidence of grade 3 or higher interstitial lung disease is as low as 3.8% (21).

No cases of grade 3 or higher pneumonitis were observed in our study (Table 3). However, after radiation therapy to the primary tumor, grade 1–2 radiation pneumonitis was observed in three cases, suggesting the importance of continuous monitoring. Additionally, the appropriate timings of radiation therapy, combination medications, duration, and treatment intensity remain important research questions for the future. In our study, among the six cases in which the primary tumor was treated, five underwent radical radiation therapy combined with chemotherapy. However, further investigation is needed to clarify whether the radiation dose was optimal, with no excess or deficiency.

Although biomarkers have yet to be identified for predicting the efficacy of ICI rechallenge following local therapy in cases resistant to ICI treatment, there seems to be value in attempting this approach, particularly for patients with good PS and oligoprogressive disease, even if the primary tumor remains. This is because reducing tumor volume and inducing an abscopal effect may be beneficial.

A key strength of our study was in the inclusion of consecutive cases in which ICI had been used as first-line therapy, which is applicable to many cases treated with recent standard therapies. However, several limitations also need to be kept in mind. The study was a small, retrospective analysis, and differences were present in the background characteristics of cases. The types of ICI and local therapies used were not standardized. In addition, the decision to perform local therapy and its content were at the discretion of the attending physician, thus introducing selection bias, as cases with a higher likelihood of improvement with local therapy were more likely to be included. Further, whether the addition of ICI rechallenge to radiation therapy is necessary remains unclear, and a comparative study between local therapy alone and local therapy with ICI rechallenge is needed.

Moving forward, prospective comparative trials with a clear definition of appropriate candidates for local therapy are necessary.

Conclusions

ICI rechallenge following local therapy in NSCLC patients who develop ICI resistance may extend PFS, suggesting that this may be a valuable therapeutic option.

Acknowledgments

The authors thank FORTE Science Communications (https://www.forte-science.co.jp/) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-3/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-3/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-3/coif). S.H. reports receiving payments for presentations from AstraZeneca K.K. and Bristol-Myers Squibb K.K. H.T. reports receiving payments for presentations from AstraZeneca K.K., MSD K.K., Bristol-Myers Squibb K.K., and Ono Pharmaceutical Co., Ltd. K.M. and H.S. report receiving payments for presentations from AstraZeneca K.K. K.S. reports receiving payments for presentations from AstraZeneca K.K., MSD K.K., and Chugai Pharmaceutical Co., Ltd. S.N. reports receiving payments for presentations from AstraZeneca K.K. and MSD K.K. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the institutional ethics committee at Funabashi Municipal Medical Center (No. 3-26) and the need to obtain individual consent for this analysis was waived based on the retrospective nature of the investigation.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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