Adjuvant immunotherapy has significantly reduced the chance of recurrence. Keynote-054 trial revealed that the adjuvant pembrolizumab led to 20% improvement in RFS compared with placebo4. However, due to the lack of deep understanding of the PD-1 blockade resistance mechanisms, mechanisms of overcoming the resistance and markers for monitoring anti-tumor activity, there is a cohort of patients suffered a recurrent disease during the adjuvant therapy or after the end of the therapy. The treatment selection of patients who relapse during or after adjuvant immunotherapy is unanswered, including treatment switch at recurrence, response rates and survival benefit. Owing to a lack of available data, there is no solution other than to follow clinical experience or enroll in a clinical trial after adjuvant therapy failure.
In our study, 59% of the recurrences were distant with or without locoregional relapse. It revealed that pembrolizumab is a more efficient adjuvant therapy in decreasing distant metastases than in decreasing locoregional recurrence, which was is consistent with data of KEYNOTE-0546. Favorable overall survival may be associated with locoregional recurrence only rather than distant metastases.
A preliminary retrospective analysis was performed to study the patterns of recurrence and salvage therapies following adjuvant anti-PD1 therapy. In this study, 70.5% of enrolled patients had melanoma recurrence during adjuvant anti-PD1 therapy and 29.5% of patients recurred following treatment cessation. The median time to relapse from commencement of adjuvant therapy was longer than data in a retrospective study conducted by Owen et al. (8 months vs. 4.6months)7.
Primary considerations for retreatment after adjuvant PD-1 failure include site of relapse, chronology of adjuvant immunotherapy and relapse, BRAF mutation status, performance status, wishes and financial status of patients.
Patients who underwent resection alone after first recurrence had a high relapse rate of 80%. These data suggest that surgery alone in the setting of melanoma relapsed after adjuvant immunotherapy may not result in long time of disease control and adjuvant systemic therapy is needed. It should be noted that no relapses were observed in three patients treated with adjuvant BRAF/MEKi after resection.
A case report revealed ipilimumab might be an effective treatment choice after adjuvant immunotherapy failure in a patient IIIC malignant melanoma8. A reported phase 2 trial of pembrolizumab combined with ipilimumab resulted in an RR of 29% in metastatic melanoma patients who have failed PD-1/L1 therapy9. However, a multi-institutional historical cohort study suggested that salvage nivolumab plus ipilimumab and ipilimumab monotherapy showed limited efficacy in Japanese populations with advanced melanoma after PD1 resistance. Nevertheless, ipilimumab was not licensed for treatment of melanoma in China and ipilimumab cannot be evaluated as a potential promising regimen.
Owen et al demonstrated that 40% of patients who recurred after cessation of adjuvant immunotherapy responded to a re-challenge of anti-PD-1 therapy7, but 12.5% of patients in the same setting experienced a response in our study. Of note, only five and eight patients were enrolled in this cohort of two studies. All the same, anti-PD1 agents rechallenge maybe an available alternative for patients ceased adjuvant immunotherapy.
To evaluate the combination of lenvatinib and pembrolizumab in patients with advanced melanoma with confirmed progression on a PD-1/L1 inhibitor, the LEAP-004 study (NCT03776136) was performed. Overall ORR was 21.4% (95% CI 13.9–30.5), DCR was 65.0% and median DOR was 6.3 months. This phase 2 study revealed lenvatinib plus pembrolizumab had activity in this population. Similarly, pembrolizumab in combination with an oral multi-targeted receptor tyrosine kinase inhibitor also may have activity in selected patients with response rate of 22.2% in our study.
An overall response rate of 82% was seen in melanoma patients treated with BRAF/MEKi after PD1 failure in a retrospective study7. BRAF/MEKi also leaded to a favorable response for BRAF-mutated melanoma in a Japanese population who relapsed after PD1 failure. In this series, our data showed a similar trend, in which patients treated with BRAF/MEKi had an ORR of 75% (3/4).
For advanced melanoma patients harboring c-Kit mutations or amplifications, imatinib mesylate is an alternative therapy with a favorable response rate of 23.3%10. In this study, no patient (0/1) responded to imatinib mesylate.
Chemotherapeutic agents were deemed to have immunomodulatory effects, such as enhancement of tumor immunogenicity and disruption of immune-suppressive pathways11–13. Chemotherapy drugs and anti-PD-1 agents showed a synergistic anti-tumor activity in non-small-cell lung cancer (NSCLC), melanoma and other cancers14,15. A retrospective study demonstrated superior event-free survival (EFS) benefit (median EFS 7.6 months in combination regimens vs. 3.4 months in monotherapies) and ORR benefit (ORR 59% in combination regimens vs. 15% in monotherapies) of chemotherapy drug combined with anti-PD-1 agent compared with monotherapy of chemotherapy drug or immune checkpoint inhibitor.
In a retrospective study conducted by Fudan University Shanghai Cancer Center, an ORR of 40% was reached in advanced melanoma patients treated with combination of pembrolizumab with temozolomide as first-line therapy, and 55% of them achieved a durable response16. We demonstrated that temozolomide plus pembrolizumab can induce clinical responses in patients whose disease progressed after adjuvant anti-PD-1 monotherapy, resulting in favorable ORR of 50%. The high ORR and short time-to-response in temozolomide plus pembrolizumab group suggested that this combination can be used to achieve rapid disease debulking. It is worth noting that 6 patients treated with temozolomide plus pembrolizumab were from Fudan University Shanghai Cancer Center.
In melanoma patients whose diseases progressed during or after adjuvant pembrolizumab, a higher objective response (approximately 26%) to subsequent chemotherapies was observed15. In this study, we demonstrated an improved ORR of the combination of carboplatin and paclitaxel, compared with that of chemotherapy historic controls in the pre-immunotherapy era17.
Additionally, we revealed that the combination of temozolomide and pembrolizumab after adjuvant anti-PD-1 therapy failure is superior to chemotherapy in the same setting.
From this data, options for first disease recurrence occurring during adjuvant anti-PD1 monotherapy or after completion of 1-year adjuvant anti-PD1 agents include surgery with adjuvant therapy, BRAF/MEK inhibitors (for BRAF mutant patients), pembrolizumab in combination with an oral multi-targeted receptor tyrosine kinase inhibitor, chemotherapeutic agents alone or with pembrolizumab. And rechallenge with PD-1 inhibitor is available for patients relapsed after completion of adjuvant PD-1 inhibition.
Despite including three large cancer centers, we could only recruit a modest number of patients. Follow-up time and imaging methods was not stringently regulated and centralised review was not performed. Due to these limitations, our results need to be further validated using a prospective study with a large sample size to minimize the heterogeneity in the population.