A proportion of cancer patients treated with immune checkpoint inhibitors (ICIs), including inhibitors of programmed cell death-1 (PD-1) and its ligand (programmed cell death ligand-1; PD-L1), have meaningful and durable clinical responses. Research is now focusing on patient selection strategies and optimal duration of therapy, as well as reinitiating therapy in patients who stop treatment for reasons other than disease progression (eg, patient/provider decision or study protocol), who may maintain long-term responses.1–3 Rechallenging patients with ICIs after discontinuation due to adverse events (AEs) has an acceptable risk/benefit profile.4 The majority of prospective and retrospective data on ICI retreatment are in patients with non-small-cell lung cancer (NSCLC) or melanoma. Reinitiation of ipilimumab, an anti-CTLA-4 antibody, in 122 patients with advanced melanoma produced an objective response rate (ORR) of 23% (5.7% complete responses (CRs) and 17.2% partial responses (PRs)).5 An observational case series explored retreatment in 13 patients with advanced solid tumors who initially responded to nivolumab or pembrolizumab and discontinued at 1 year; of the eight (61.5%) patients who progressed off treatment and were retreated, two had PRs and six had stable disease (SD).6 In the KEYNOTE-001 trial, one patient with NSCLC had a PR with retreatment after responding to initial therapy. Among 14 retreated patients in the KEYNOTE-010 trial, six had a PR.7 8 An analysis of 16 patients with advanced NSCLC who had survived at least 5 years after starting nivolumab treatment showed responses in the two patients who were retreated with an anti-PD-1 agent after progression.9 In a prospective phase IIIb/IV safety study (CheckMate 153), limited clinical benefit was seen in patients with NSCLC who progressed after the initial 12-month nivolumab treatment period and underwent retreatment; the median duration of retreatment was 3.8 months.10 Furthermore, progression-free survival (PFS) was improved in patients who received continuous nivolumab therapy versus those who received an initial 12 months of treatment and were subsequently eligible for retreatment. The optimal treatment sequence and duration with ICIs remains unclear.

Here we report the effects of retreatment with durvalumab, a PD-L1 inhibitor, in patients who discontinued treatment without disease progression in Study 1108, a phase I/II trial in advanced solid tumors (NCT01693562).

The study design and initial results of this multicenter, open-label study have been described previously.11–13

This study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Council on Harmonization guidelines on Good Clinical Practice, any applicable laws and requirements, and any conditions required by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee that has approved this study to be conducted in its territory. The study protocol was reviewed and approved by the Institutional Review Board or Ethics Committee of the participating centers, and informed consent was obtained.

The clinical data set analyzed here may be obtained in accordance with AstraZeneca’s data sharing policy, which is described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

This study demonstrates that retreatment with durvalumab can be safe and effective in patients who stop treatment and progress while off therapy. Of the 70 retreated patients, more than 70% experienced clinical benefit (11.4% with PR and 60.0% with SD). This suggests that retreatment restored antitumor activity in a majority of patients, resulting in high rates of durable disease control with an acceptable safety profile. Despite its retrospective design, the study had multiple strengths, including the analysis of the largest retreatment cohort in this setting, the inclusion of diverse tumor types, and treatment homogeneity.

There are no established guidelines for optimal duration of initial therapy with ICIs. In clinical practice and in many research protocols, patients are treated through the first evidence of disease progression to account for tumor flare (pseudoprogression) and to provide adequate time for ICI activity to become apparent, which may take longer than with conventional cytotoxic chemotherapies. In patients who are benefiting from ICIs, treatment may continue for 2 years or even longer.14 15 Patients and providers hesitate to discontinue treatment without disease progression. However, indefinite treatment raises concerns about long-term safety, costs, and quality of life. The outcomes of this study permit a more informed decision process.

Information on retreatment with ICIs is limited, with previous studies largely conducted in NSCLC or melanoma. In a study of pembrolizumab for metastatic melanoma, patients with CRs discontinued therapy after >6 months. Four patients developed disease recurrence and were retreated with pembrolizumab; one had CR, one had SD, and the remaining two had PD.1 Similarly, in a retrospective study of anti-PD-1 monotherapy for metastatic melanoma, 5/34 patients responded to retreatment.16 In a rechallenge series of 144 patients with NSCLC who discontinued initial ICI treatment, retreatment PFS was longer in those who discontinued due to toxicity or clinical decision than in those who discontinued due to disease progression.17 In a retrospective study, patients with NSCLC who had SD or progressive disease in response to atezolizumab or durvalumab were switched to nivolumab or pembrolizumab; among the 13 evaluable patients, four had SD and nine had disease progression with a short PFS.18 The differences between these data and the current study indicate that retreatment should be reserved for patients who benefit from initial ICI therapy.

In the present study, ORR2 was significantly lower than ORR1 (11.4% vs 55.7%, p<0.01). Despite small numbers, objective responses were observed in UC (3/8) and NSCLC (3/21), which are immunotherapy-sensitive tumors.19 20 Furthermore despite low ORR2, 34/66 patients (51.5%) with evaluable scans had a decrease in on-treatment tumor volume compared with baseline (figure 2), indicative of meaningful clinical benefit.

The rates of response and disease stability, and the duration of clinical benefit were comparable to those of second-line or later-line chemotherapy regimens following immunotherapy.21 22 The high rates of durable disease control (DCR2 24) and PFS2 suggest the possibility of immune rescue and restoration of immune memory. Importantly, differences were observed based on tumor types and PD-L1 expression. For example, >90% of patients with MSI-high tumors had SD, which exceeded 24 weeks in 58.3%. This is likely due to both tumor-cell intrinsic genetic and immune-related features. MSI-high tumors have increased tumor-infiltrating lymphocyte density relative to microsatellite-stable tumors,23 and higher rates of CD8+ T-cell infiltration, PD-L1 expression, and IFNγ production.24–26 Similarly with PFS2, the highest 12-month rate was in UC (62.5%), which is particularly immunotherapy-sensitive at high grades.19 The lowest rate was in HNSCC (0%), which may not be a disease-specific phenomenon but rather explained by tumor-specific factors such as human papilloma virus and smoking status.

Patients with PD-L1 high expression at baseline demonstrated higher ORR2 and DCR2 24, and longer median DoR2 than patients with low/negative expression. Additional research is needed on other potential predictive biomarkers such as tumor mutational burden, oncogenic driver mutations, and circulating DNA mutant allele fractions.

The durability of disease control with durvalumab retreatment in Study 1108, evidenced by a DCR2 24 of 47.1% across the 14 primary tumor types, represents a clinically meaningful benefit in a heavily pretreated patient population. Most randomized trials involving ICI retreatment are in NSCLC and melanoma, with relatively few patients in each study entering retreatment. Furthermore, they often focus more on disease control rate than on its duration, giving a limited picture of longer-term therapeutic benefits. In KEYNOTE-010, a DCR2 of 78.6% was recorded in 14 patients with advanced NSCLC who were retreated with pembrolizumab.8 In KEYNOTE-024, the DCR2 was 70% in a treatment-naïve patient population with NSCLC.27 In the present study, DCR2 was 52.4% in the 21 patients with NSCLC and DCR2 24 was 33.3%, indicating that long-term clinical benefit may be possible for many patients who experience disease control with durvalumab retreatment. Among the 13 patients with metastatic melanoma who underwent retreatment with pembrolizumab in the KEYNOTE-006 study, the DCR2 was 76.9%.28 Crucially, only 2/71 patients in the retreatment population of Study 1108 had melanoma, a tumor with high sensitivity to immunotherapy; therefore, only limited inference can be made through comparison with studies focusing solely on patients with melanoma.

The durability of clinical benefit varied among patients who completed 1 year of initial durvalumab treatment. No patients remained progression-free at the data cut-off for the current analysis, regardless of whether they were retreated. However, among the patients who were retreated, the interval time without progression differed greatly—some patients remained off treatment for over 1 year and had an OS of over 3 years from the start of initial therapy (figure 1). Of the retreated patients, five had a BOR2 of PR that was ongoing at the data cut-off, with some lasting for over 1 year.

The study had important limitations. Only 168/1022 patients (16.4%) in the initial durvalumab treatment population were eligible for retreatment, suggesting that the results only apply to a select patient population. Small patient numbers per individual tumor type precludes tumor-specific recommendations. Much remains unknown about the complex factors that influence tumor immunogenicity and checkpoint inhibitor efficacy in retreatment. Patients in the present study were limited to a maximum of 1 year of retreatment with durvalumab; however, this stipulation has not been included in subsequent clinical trials of this agent. Importantly, there are currently no formal guidelines regarding the appropriate duration of initial treatment or retreatment with ICIs. This study was retrospective and future research should prospectively evaluate clinical benefit using a control arm.

The encouraging safety and efficacy data, particularly the high DCR2 24 rate and the long DoR2, support durvalumab retreatment in patients who progress after a planned treatment stop following initial benefit. Future research should explore mechanisms of retreatment activity and discontinuation after shorter initial treatment periods.