- Ipilimumab:
- Is a humanized monoclonal antibody that blocks CTLA-4:
- A key regulatory molecule of the immune system
- The use of immune checkpoint blockade via monoclonal antibodies targeting anti-CTLA4 (ipilimumab; Yervoy):
- Has been established as an effective treatment for stage IV disease since 2011
- Although approved in the metastatic setting for some time:
- The use of checkpoint blockade in the adjuvant setting has been more recently approved in stage III melanoma:
- Based on a number of randomized phase III trials
- The randomized phase III clinical trial EORTC 18071 compared high-dose ipilimumab (10 mg/kg) to placebo, administered every 3 weeks for four doses, then every 3 months for 3 years unless toxicity or relapse prevented its continuation:
- It demonstrated both a decreased rate of recurrence and improved OS for patients in the ipilimumab arm, leading to the approval of adjuvant ipilimumab
- Despite the survival benefits noted in this adjuvant setting, opponents of this approach remark on the toxicity and paradoxical increased dosing seen in the adjuvant setting compared to metastatic disease (the latter of which employs a dose of 3 mg/kg every 3 weeks × four doses)
- The toxicity from ipilimumab in EORTC 18071 was significant: adverse events of any grade were noted in 98.7% of patients treated with ipilimumab, including 54.1% with grade 3 or 4 toxicity
- The median number of ipilimumab doses was four
- Furthermore, there were five treatment-related deaths in patients treated with ipilimumab (three due to colitis, one to myocarditis, and one to multiorgan failure associated with Guillain–Barré syndrome)
- While treatment-related deaths may be encountered in any clinical trial, such events in the adjuvant setting raise caution; some argue whether the toxicity is worth the potential survival benefit
- This is relevant since there is a fraction of patients who will never recur and therefore have no potential to benefit from any adjuvant therapy
- Of course, the challenge is that it is currently not possible to know that information at the level of an individual patient:
- Therefore, the ability to prospectively identify higher- and lower-risk patients with biomarkers remains an area of intense clinical interest, as is interest on additional targets and combination therapies
- The use of checkpoint blockade in the adjuvant setting has been more recently approved in stage III melanoma:
- Is a humanized monoclonal antibody that blocks CTLA-4:
- Following the success and approval of CTLA-4 inhibition:
- The study of programmed cell death protein-1 (PD-1) axis:
- Which functions in the periphery to modulate T-cell responses, has produced success in a number of clinical trials
- The study of programmed cell death protein-1 (PD-1) axis:
- PD-1 interacts with two ligands:
- PD-L1 and PD-L2:
- To dampen T-cell responses:
- Physiologically functioning to limit autoimmunity
- To dampen T-cell responses:
- The inhibitory effect of PD-1 is accomplished through a dual mechanism of:
- Promoting apoptosis in cytotoxic T-cells (programmed cell death, as the name implies) while simultaneously reducing apoptosis in regulatory T cells
- PD-1 protein is upregulated on activated T cells:
- Blockade of this molecule upregulates the cellular immune system’s antitumor activity
- In a randomized, double-blind, phase III clinical trial (CheckMate 238) for patients with resected advanced melanoma, over 900 patients who underwent complete resection of stage IIIB, IIIC, or IV melanoma received either nivolumab (3 mg/kg every 2 weeks) or ipilimumab (10 mg/kg every 3 weeks × 4 doses and then every 12 weeks):
- Toxicity (grade 3 or 4 adverse events) was reported in 14.4% of the patients in the nivolumab group versus 45.9% of patients in the ipilimumab group; moreover, two deaths (0.4%) were reported and noted to be related to toxic effects in the ipilimumab group
- Weber et al. concluded that nivolumab resulted in:
- Significantly longer RFS and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab
- Based upon the results of CheckMate 238:
- Nivolumab was approved for adjuvant use by the FDA in 2017
- Another anti–PD-1 drug, pembrolizumab, was compared to placebo in the randomized, controlled, double-blind phase III EORTC 1325-MG/KEYNOTE-054 trial:
- AJCC 7th edition stage IIIA (if stage IIIA, SLN deposit had to be >1 mm metastasis), IIIB, and IIIC completely resected patients were included:
- RFS was 59.8% in the 514 patients receiving pembrolizumab versus 41.1% in the 505 patients on placebo after 42 months of follow-up (HR 0.59; 95% CI, 0.49 to 0.70) in the updated trial results published in 2021
- Pembrolizumab was approved by the FDA for adjuvant use in stage III disease in 2019 after the initial trial results were released
- AJCC 7th edition stage IIIA (if stage IIIA, SLN deposit had to be >1 mm metastasis), IIIB, and IIIC completely resected patients were included:
- Building on the success of pembrolizumab in the stage III adjuvant setting, the phase III randomized clinical trial KEYNOTE-716 trial studied adjuvant pembrolizumab versus placebo in resected stage IIB or IIC melanoma patients, all of whom had a negative SLN biopsy:
- At the second interim analysis with a median follow-up of 18 months:
- This study demonstrated a significant reduction in relapse-free survival and distant metastasis among patients receiving pembrolizumab in an overall cohort of 1,182 patients
- These findings led to the recently expanded indication for the use of pembrolizumab in the stage IIB and IIC setting
- At the second interim analysis with a median follow-up of 18 months:
- PD-L1 and PD-L2:
- As the indications continue to expand for the use of checkpoint blockade, their utilization in the metastatic, adjuvant, and neoadjuvant setting must be considered in view of their side effect profile:
- Adverse events become increasingly important to the surgical oncologist as immunotherapy is increasingly utilized in the adjuvant and neoadjuvant settings
- Multidisciplinary care is ultimately crucial to these decisions in weighing the risks of a particular side effect profile, its potential downstream effects, and the potential benefit of these therapies
Rodrigo Arrangoiz MS, MD, FACS, FSSO 