Predictive models for response and survival in patients treated with anti-PD-1 monotherapy or with anti-PD-1 and ipilimumab combination: editorial commentary
In the article titled, “Clinical models to define response and survival with anti-PD-1 antibodies alone or combined with ipilimumab in metastatic melanoma” published in the April 2022, issue of Journal of Clinical Oncology, authors present a predictive model for efficacy using clinical parameters that are routinely available in the clinic at the time of treatment initiation (1). Authors mainly present the risk calculator tool to predict objective response rate (ORR), progression-free survival (PFS), overall survival and the treatment selection tool to identify patients who may benefit from combination therapy over monotherapy.
Programmed death 1 (PD-1) blockers is one of the most successful class of anti-cancer therapy that dramatically changed the course of treatment and survival outcomes for metastatic melanoma (2-10). Combination of PD-1 blockers (nivolumab and pembrolizumab) and CTLA-4 blockers (ipilimumab) has demonstrated potential in further improving the outcomes and has been approved for different types of cancers including metastatic melanoma, metastatic NSCLC with no EGFR or ALK aberrations, untreated advanced renal cell carcinoma, metastatic colorectal carcinoma, metastatic hepatocellular carcinoma and metastatic mesothelioma (Table 1). Most recently, tremilimumab a second CTLA-4 blocker was approved in combination with PD-L1 blocker, durvalumab for metastatic NSCLC (11).
Table 1
| Indication | Regimen |
|---|---|
| Metastatic melanoma | Nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day, every 3 weeks for 4 doses. After completion of 4 doses, nivolumab is administered as single agent at recommended dose |
| Renal cell carcinoma | Nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg on the same day, every 3 weeks for 4 doses. After completion of 4 doses, nivolumab is administered as single agent at recommended dose |
| Colorectal carcinoma with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)** | Nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg on the same day both administered as 30-minute intravenous (IV) infusion, every 3 weeks for 4 doses. After completion of 4 doses, nivolumab is administered as single agent at recommended dose |
| Hepatocellular carcinoma** | Nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day both administered as 30-minute intravenous (IV) infusion, every 3 weeks for 4 doses. After completion of 4 doses, nivolumab is administered as single agent at recommended dose |
| Metastatic non-small cell lung cancer | Ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks |
| Malignant pleural mesothelioma | Ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks |
| Esophageal cancer | Ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks |
*, summarized from package insert in December 2022; **, accelerated approval, continued approval contingent upon verification and description of clinical benefit in confirmatory trials. PD-1, programmed death 1.
In metastatic melanoma patients with unresectable tumors who were expected to have an ORR of approximately 10% with standard of care (SoC) chemotherapy, PD-1 monotherapy reported an ORR of 32% in clinical studies (Table 2). The hazard ratio (HR) for overall survival was 0.42 and the HR death or disease progression was 0.43 compared to SoC dacarbazine therapy for anti-PD-1 monotherapy indicating an improvement of survival outcomes by >50% over SoC (12,13). The ORR improved further to >50% with PD-1 and ipilimumab combination (15-17). Median progression free survival (PFS) was also improved further with combination of ipilimumab and PD-1 blockers (Table 2). PFS was 6.9 months for monotherapy and 11.5 months for combination (14). Anti-PD-1 plus ipilimumab combination therapy further improved the outcomes as seen by HR for death or disease progression of 0.42 in favor of combination over ipilimumab monotherapy and 0.74 in favor of the combination over anti-PD-1 monotherapy (14).
Table 2
| Study details (reference) | Efficacy outcomes | Adverse events |
|---|---|---|
| Phase 3 RCT comparing nivolumab versus chemotherapy in patients who progressed after anti-CTLA-4 treatment (12) | ORR, 32% vs. 11%; median PFS, 4.7 vs. 4.2 months; 6-mo PFS rate, 48% vs. 34% respectively | Grade 3–4 drug-related serious AEs, 5% vs. 9% respectively. Most common serious AEs (any grade) in nivolumab group were fatigue, pruritus and diarrhea |
| Phase 3 RCT comparing nivolumab versus dacarbazine in previously untreated patients without BRAF mutation (13) | ORR, 40% vs. 14%; 1-year OS rate, 73% vs. 42%. HR for death, 0.42; median PFS, 5.1 vs. 2.2 months respectively; HR for death or a progressive disease, 0.43 | Grade 3–4 drug-related serious AEs, 6% in each cohort. Most common serious AEs (any grade) in nivolumab group were fatigue, pruritus and nausea |
| Phase 3 RCT comparing nivolumab plus ipilimumab versus monotherapy (nivolumab or ipilimumab) in previously untreated patients (14) | ORR, 58% in combination vs. 44% with nivolumab and 19% with ipilimumab monotherapy; median PFS, 11.5 vs. 6.9 months and 2.9 months respectively. HR for disease progression 0.74 and 0.42 compared to nivolumab and ipilimumab monotherapy respectively | Grade 3–4 drug-related AEs, 55% with combination vs. 16% with nivolumab and 27% with ipilimumab. Most common AEs in combination cohort were diarrhea, fatigue and pruritus |
PD-1, programmed death 1; RCT, randomized controlled trial; ORR, objective response rate; PFS, progression-free survival; AEs, adverse events; HR, hazard ratio.
Though PD-1 monotherapy and combination with ipilimumab drastically improved the survival outcomes, significant proportion of patients still do not respond but can develop severe adverse events and even the patients who respond, significant fraction of patients develop treatment-limiting adverse events (5). Given the high cost of immunotherapy and the financial burdens associated with treatment failure as well as management of severe adverse events it is important to identify patients who are likely to respond to monotherapy, patients who may need combination therapy and more importantly patients who may not respond before the initiation of the treatment. While biomarker assessments and companion diagnostics are intended to help in patient selection, they are associated with additional time and costs. Furthermore, tertiary health care institutions especially the ones in the rural areas may not be equipped with assays and instruments to estimate the expression of biomarkers in the tumor tissues. Predictive models and tools proposed by Pires da Silva et al. which are based on parameters routinely available in almost all the clinics can be very helpful in the patient selection (1).
To develop risk calculators to define efficacy outcomes, authors performed a multicenter retrospective cohort study from consecutive patients with metastatic melanoma treated with anti-PD-1 or combination of ipilimumab and anti-PD-1 between December 2009 and April 2020. Sixteen melanoma centers in Australia, the United States, and Europe participated in the study and data from 1644 metastatic melanoma patients were included in the analyses. Patients were divided in three cohorts including the discovery cohort (n=633), validation-1 cohort (n=419) and validation-2 cohort (n=592). Nomograms for prediction were based on clinical parameters such as ECOG score, hemoglobin, lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), presence or absence of metastasis (lung, liver and brain), line of treatment and treatment administered (monotherapy or combination therapy), which are easy to obtain in most tertiary clinics. Nomograms were calculated for ORR, PFS and OS for anti-PD-1 monotherapy and ipilimumab plus anti-PD-1 combination. Interestingly, majority of clinical parameters used in the risk calculators including ECOG score, LDH, NLR, presence or absence of liver metastasis, line of treatment and treatment administered overlapped for ORR, PFS and OS. Hemoglobin and brain metastases were not identified as risk factors for ORR whereas lung metastasis was not found to be a risk factor for PFS and OS. The parameters identified for treatment selection were slightly different and the model was based on melanoma primary site, mutation status, LDH and NLR. The predictive models developed by authors had a reasonably high sensitivity and specificity with area under the curve (AUC) of 0.71, 0.68, 0.77 and 0.73 for ORR, PFS, OS and treatment selection respectively. Authors noted that patients with predicted response to ipilimumab plus anti-PD-1 significantly higher than the anti-PD-1 monotherapy may benefit from combination and the treatment selection for remaining patients should carefully assessed on a case-by-case basis.
The findings are striking because the nomograms developed in this study are based on routine clinical parameters that are available in almost all the clinics and can be easily applied at the time of treatment initiation without the help of advanced statistical programs. The study used independent cohorts (validation 1 and 2) to confirm and validate the findings from their discovery cohort. Validation of findings in additional independent cohorts can further strengthen the confidence in the findings. As authors point out, one of the important features of the proposed model is the ability to identify non-responders which can be very helpful to the treating physician in identifying the patients who are less likely to respond to anti-PD-1 monotherapy or combination with ipilimumab. Clinicians may start considering other options like targeted therapy or enrolling in clinical trials for patients who are less likely to respond. Another important finding from the study that needs further research is the differential association of sites of metastases such as liver, lung and brain with response and survival but not treatment selection. While liver metastasis was associated with both response and survival, lung metastasis was associated with response but not survival and brain metastasis was associated with survival but not response. Translational studies can further dissect the significance of site of metastasis in response to anti-PD-1 monotherapy or combination therapy and survival of the patient following treatment.
While the findings are significant, based on decent number of patients and validated using independent cohorts there is room for improvement in the specificity and sensitivity of the models. The findings also need to be replicated by independent centers in larger cohorts to gain wide application in tertiary centers. Recently researchers from FDA published a cross-study analyses of risk factors in chimeric antigen receptor T cells (CAR-T cells) based on voluntarily submitted sponsor data across 17 phase 1 and 2 studies in 1,926 patients through a FDA database pilot project (18). Similar initiative can be extended to rich data submitted for PD-1 blockers and combinations to externally validate the findings from this study. Another important question that can be addressed in future studies is whether same risk factors can be applied to decision making in high-risk resectable melanoma and to predict response and survival in other cancer types such as lung cancer, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma and mesothelioma for which the combination of ipilimumab and anti-PD-1 antibodies has been approved. Finally, similar predictive models are needed to identify patients who are likely to develop treatment-limiting AEs and research is needed to evaluate whether treatment given to manage immune-related AEs could limit the benefits from immunotherapy (19,20).
In summary, authors proposed an easily applicable model to identify responders (and non-responders) to anti-PD-1 monotherapy and patients who may benefit from ipilimumab and anti-PD-1 combination in metastatic melanoma. The risk calculator can also predict PFS and OS in metastatic melanoma patients. The models proposed in the study need to be validated by independent centers with larger cohorts and can supplement but not replace as the authors also point out, the best clinical judgement of the treating physician and risk-benefit analysis of each treatment approach. The findings encourage translational research on association between sites of metastases and clinical outcomes and further studies in other cancer types.
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6564/coif). AR is currently employed at Arcellx, a clinical stage biotech developing cell-based treatments for cancer, and received stock or stock options from Arcellx. Arcellx did not provide funding to this article and did not provide additional benefits as salary or stocks to the author for writing this article. The author has no other conflicts of interest to declare.
Ethical Statement: The author is 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.
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