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. Author manuscript; available in PMC: 2023 Dec 8.
Published in final edited form as: Nat Med. 2023 Aug 17;29(9):2278–2285. doi: 10.1038/s41591-023-02498-y

Ipilimumab with or without nivolumab in PD1/PDL1 blockade refractory metastatic melanoma: a randomized phase 2 trial

Ari VanderWalde 1,*, Shay L Bellasea 2,3, Kari L Kendra 4, Nikhil I Khushalani 5, Katie M Campbell 6, Philip O Scumpia 6, Lawrence F Kuklinski 6, Frances Collichio 7, Jeffrey A Sosman 8, Alexandra Ikeguchi 9, Adrienne I Victor 10, Thach-Giao Truong 11, Bartosz Chmielowski 6, David C Portnoy 1, Yuanbin Chen 12, Kim Margolin 13,#, Charles Bane 14, Constantin A Dasanu 15, Douglas B Johnson 16, Zeynep Eroglu 5, Sunandana Chandra 8, Egmidio Medina 6, Cynthia R Gonzalez 6, Ignacio Baselga-Carretero 6, Agustin Vega-Crespo 6, Ivan Perez Garcilazo 6, Elad Sharon 17, Siwen Hu-Lieskovan 18, Sapna P Patel 19, Kenneth F Grossmann 18,¥, James Moon 2,3, Michael C Wu 2,3, Antoni Ribas 6,*
PMCID: PMC10708907  NIHMSID: NIHMS1939923  PMID: 37592104

Abstract

In this randomised phase 2 trial, blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4) with continuation of programmed death receptor 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1/L1 therapy and whose tumours progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of the ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included difference in CD8 T cell infiltrate among responding and non-responding tumours, objective response rate (ORR), overall survival (OS) and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in PFS over ipilimumab (hazard ratio of 0.63, 90% CI 0.41, 0.97, one-sided p-value of 0.04). Objective response rates were 28% (90% CI: 19%, 38%) and 9% (90% CI: 2%, 25%), respectively (one-sided p-value of 0.05). Treatment-related adverse events of grade 3 or higher occurred in 57% and in 35%, respectively, consistent with the known toxicity profile of these regimens. The change in intratumoural CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576.

Introduction

At the time of study design, treatment with PD-1 blocking antibodies was the most widely used standard-of-care front-line therapy for patients with metastatic melanoma 1–4. The optimal therapeutic approach for patients who do not respond to initial single agent anti-PD-1 treatment remains unclear. We reasoned that we could potentially reverse resistance by addressing the main mechanism of lack of response to PD-1 blockade, the absence of pre-existing intratumour T cell infiltrates 5,6. It is possible that an immune checkpoint such as the cytotoxic T lymphocyte antigen-4 (CTLA-4), which inhibits T cell proliferation at the time of T cell activation, limits the ability of anti-tumour T cells to infiltrate cancer lesions 7,8. CTLA-4 blockade with therapeutic antibodies allows T cells to expand, circulate and infiltrate tumours, as demonstrated in mouse models 9–11. Similarly, in humans, CTLA-4 blocking antibodies induce cell proliferation in lymphoid organs, diversify the peripheral immune response, and increase intra-tumour T cell infiltration 12–16. Upon reaching tumours, T cells can still become negatively regulated by the reactive expression of PD-L1 on tumours and other cells of the immune tumour microenvironment 17, arguing that there may be a benefit for combined CTLA-4 and PD-1 blockade therapy, over CTLA-4 blockade alone, to reverse primary resistance to anti-PD-1. The concept of combined CTLA-4 and PD-1 blockade to reverse resistance to PD-1 blockade alone is supported by three published clinical trials, one retrospective 18 and two prospective 19,20.

The SWOG Cancer Research Network clinical trial S1616 is a randomised phase 2 study to address the scientific question whether CTLA4 blockade, alone or in combination with continued PD-1 blockade, could reverse resistance to prior anti-PD-1 sequentially or concomitantly. All patients had advanced melanoma with primary resistance to anti-PD1/L1 inhibitors, defined as tumours having no objective clinical response (complete or partial response) to the prior use of anti-PD1 or anti-PD-L1 blocking agents without intervening therapy for advanced disease, or with recurrence while on adjuvant anti-PD-1 therapy. The clinical trial was designed to test the hypothesis that combination nivolumab plus ipilimumab is superior to single-agent ipilimumab in terms of progression-free survival (PFS) in this anti-PD1/L1-experienced population, with the analysis of changes in intratumour infiltration by CD8 T cells as a secondary endpoint. A 3:1 randomisation was used to power a secondary objective to evaluate changes in CD8 T cell infiltration of biopsies of patients in the combination group, requiring a larger number of patients receiving the combination. We anticipated that the benefit of the combination would manifest itself through improved PFS mediated by increasing intratumour CD8 T cell infiltration upon releasing the CTLA-4 immune checkpoint with continued PD-1 blockade therapy 6–8,10. This clinical trial was open at 39 academic sites across the U.S.A. Detailed experimental methods are provided in the Methods and in the Reporting Summary.

Results

Study Population

Between July 17, 2017 and July 15, 2020, 94 patients were registered into this non-blinded, randomised study. Of these, 92 met eligibility criteria (two were found to be ineligible after registration and excluded from analyses) and 91 received study therapy, as one patient in the combination arm refused the therapy as randomised due to new onset diagnosis of diabetes; 68 received nivolumab plus ipilimumab and 23 patients received ipilimumab alone (Figure 1). The primary endpoint analysis was performed once the protocol-specified anticipated number of 78 events had occurred, with data lock of March 9, 2022, at a time when the median follow up among patients last known to be alive and progression-free was 28 months (range 4–40 months). This data lock date was used for the PFS analysis, as it was event-driven and conducted at the specified event timing per protocol design. All other analyses used the final data lock date of November 3, 2022, when the median follow up among patients last known to be alive was 36 months (range 4–55 months), to provide the most accurate and recent assessment of disease outcomes and toxicities. The randomised groups were generally well balanced (Table 1), including related to the time from ending prior anti-PD-1/L1 therapy and starting on the S1616 protocol treatment (Supplementary Table 1). All eligible patients had received prior anti-PD-1 therapy without intervening therapy, with 10% in the combination group and 13% in single agent group having received anti-PD-1 therapy in the adjuvant setting.

Figure 1. CONSORT diagram.

Figure 1.

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The diagram includes patient enrolment, randomisation and follow up. All eligible patients who were randomised were included in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment that they were randomly assigned.

Table 1.

Patient and disease characteristics.

Characteristic Ipilimumab (n=23) Nivolumab + Ipilimumab (n=69) P
Age (years) 69 (40, 91) 64 (34, 90) 0.55
Age
 < 65 years 9 39% 35 51% 0.47
 ≥ 65 years 14 61% 34 49%
Sex
 Male 15 65% 46 67% 1
 Female 8 35% 23 33%
Race
 White 22 96% 63 91% 1
 Black 0 0% 1 1%
 Asian 1 4% 3 4%
 Unknown 0 0% 2 3%
Performance Status
 0 15 65% 45 65% 0.85
 1 6 26% 20 29%
 2 2 9% 4 6%
LDH at baseline
 Elevated LDH 6 26% 9 13% 0.18
 Normal LDH 5 22% 28 41%
 LDH Not Done 12 52% 32 46%
AJCC melanoma classification
 Stage III 6 26% 12 17% 0.37
 Stage IV 17 74% 57 83%
Adjuvant therapy
 No prior adjuvant therapy 17 74% 58 84% 0.22
 Adjuvant PD-1 3 13% 7 10%
 Adjuvant BRAF/MEK 0 0% 2 3%
 Other Adjuvant Therapy 3 13% 2 3%
Prior metastatic therapy
 Adjuvant Therapy Only 1 4% 6 9% 0.51
 Anti-PD-1 only 20 87% 54 78%
 BRAF/MEK followed by PD-1 1 4% 1 1%
 Other anti-PD-1 combination 1 4% 8 12%
Duration of prior anti-PD-1/PD-L1 therapy
 < 6 Months 15 65% 44 64% 1
 ≥ 6 Months 8 35% 25 36%
Brain/CNS involvement at baseline
 Yes 2 9% 5 7% 1
 No 21 91% 64 93%
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Legend. Patient characteristics among randomized patients. Median (range) and N (%) reported. Two-sided p-values from Wilcoxon (quantitative covariates) and Fisher’s exact (categorical covariates) reported.

Efficacy

PFS was significantly longer with combination therapy versus ipilimumab therapy alone (HR= 0.63, 90% CI 0.41–0.97, p=0.04, pre-specified one-sided alpha 0.1; Figure 2A). The 6-month PFS estimates were 34% (90% CI: 25%−43%) and 13% (4%−27%) for the combination therapy versus ipilimumab alone groups, respectively. The PFS benefit of the combination therapy was consistent when analysing different subgroups, although subgroups with fewer than 10 subjects did not provide reliable data (Figure 2B). S1616 was not powered to detect differences in OS, and survival data was collected as a secondary endpoint; there was no significant difference between the two groups as of the last data lock of November 3, 2022 (HR 0.83, 90% CI 0.50–1.39, p=0.28, Extended Data Figure 1).

Figure 2. Analysis of progression-free survival (PFS).

Figure 2.

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A) Kaplan-Meier estimates of PFS as assessed by local investigators. The 6-month PFS estimates were 34% (90% CI: 25%−43%) and 13% (4%−27%) for the combination therapy versus ipilimumab alone groups, respectively. B) Forest plot for PFS according to subgroups. The hazard ratio (HR) and 90% confidence interval (CI) from a Cox regression model are reported and represented by the solid black squares and error bars; no adjustment was made for multiple comparisons.

Objective response rate (ORR, defined as a complete or partial response to therapy per RECIST version 1.1), also reported based on an analysis of data that were complete as of November 3, 202221, was 28% (90% CI 19% - 38%) in the combination therapy group and 9% (90% CI 2%- 25%) in the ipilimumab alone group (p=0.05, one-sided Fisher’s exact test). As this was not the primary endpoint, no threshold for significance was pre-specified and p-values should be interpreted qualitatively. Eight patients (12%) receiving combination therapy achieved a complete response (CR), and 11 (16%) a partial response (PR). No patients on ipilimumab alone achieved a CR, and two (9%) achieved a PR (Figure 3A and 3B, and Supplementary Table 2). Best response by change in sum of target lesions for combination therapy and ipilimumab alone can be seen in Figures 3A and 3B, respectively. Among patients with response to therapy, the two patients receiving ipilimumab alone had ongoing responses of 16+ and 33+ months, respectively, while 9 of 19 (47%) patients in the nivolumab plus ipilimumab group continued in response over a range of 6+ to 37+ months. The median duration of response in the nivolumab plus ipilimumab group was 40.9 months (90% CI 8 – NR) (Figure 3C), while it could not be estimated for the patients in the ipilimumab alone group due to the small sample size.

Figure 3. Depth of response and response duration.

Figure 3.

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A and B) Waterfall plots of overall response in the nivolumab and ipilimumab group (A) and the ipilimumab group (B). The plots show the change in RECIST target lesions. Lines indicate threshold for objective response (≥30% decrease) or disease progression (>20% increase). Asterisks and hatched bars denote patients whose best response was progression due to new lesions (n=23 with nivolumab and ipilimumab, and n=14 with ipilimumab) or clear worsening of non-measurable disease (n=2 with nivolumab and ipilimumab) without assessable RECIST changes, symptomatic deterioration (n=1 with nivolumab and ipilimumab, and n=1 with ipilimumab), or death due to disease (n=2 with nivolumab and ipilimumab, and n=1 with ipilimumab). Two patients on the combination group with changes in RECIST measurements greater than 100% over baseline are denoted on the far left with hatched bars capped at 100%. Two patients on the combination group did not have complete follow-up disease assessment data and were not included. C) Swimmer’s plot of the course of patients with an objective response to therapy. Bars represent progression-free survival (PFS) from time of registration. Patients with arrows are alive and progression-free.

Toxicity

In the nivolumab plus ipilimumab group, 34 patients (50%) experienced a maximum of grade 3 treatment-related adverse events, four patients (6%) experienced a grade 4 adverse event and one patient (1%) experienced a grade 5 adverse event (disseminated intravascular coagulation) (Table 2). In the combination arm, 20 patients (29%) discontinued protocol therapy due to toxicity. In the ipilimumab alone group, five patients (22%) experienced a maximum of grade 3 treatment-related adverse events, two patients (9%) experienced grade 4 adverse events, and one patient (4%) experienced a grade 5 adverse event (colonic perforation). In the ipilimumab alone arm, 4 patients (17%) discontinued therapy due to toxicity. In both groups, the most frequent grade 3 or higher adverse event was diarrhoea. There was no significant difference between the groups for any individual grade 3 or higher adverse event, but total grade 3 or higher adverse events was numerically higher with the combination, 57%, compared to single agent ipilimumab, 35% (p-value = 0.09).

Table 2.

Grade 3 or higher treatment-related toxicities in at least 4% of patients on either arm.

Event Ipilimumab (N=23) Nivolumab + Ipilimumab (N=68)
Diarrhea 3 (13%) 9 (13%)
AST Increased 2* (7%) 5 (7%)
ALT Increased 2* (7%) 5 (7%)
Rash 1 (4%) 4 (6%)
Fatigue 1 (4%) 4 (6%)
Anemia 0 (0%) 4 (6%)
Hypotension 0 (0%) 4 (6%)
Hyponatremia 1 (4%) 4* (6%)
Pruritus 0 (0%) 3 (4%)
Vomiting 0 (0%) 3 (4%)
Endocrine Disorders (Other) 0 (0%) 3 (4%)
Alkaline Phosphatase Increased 1 (4%) 2 (3%)
Colitis 0 (0%) 3* (4%)
Hypokalemia 0 (0%) 3* (4%)
Adrenal Insufficiency 1 (4%) 3* (4%)
Atrial Fibrillation 1 (4%) 1 (1%)
Bilirubin Increased 1 (4%) 0 (0%)
Hypophosphatemia 1 (4%) 0 (0%)
Hyperglycemia 1* (4%) 0 (0%)
Colonic Perforation 1 (4%) 0 (0%)
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*

1 each of these events was grade 4.

Legend. All adverse events reported were assessed as possibly, probably, or definitely related to study treatment. To be included in the safety analysis, patients must have received at least one dose of protocol therapy. Adverse event severity was scored using NCI Common Terminology Criteria for Adverse Events version 4.0. One patient in the ipilimumab arm had a grade 5 Adverse Event (death) due to colonic perforation. One patient in the nivolumab plus ipilimumab arm had a grade 5 Adverse Event (death) due to disseminated intravascular coagulation.

Changes in CD8 T-cell density

Changes in CD8 T cell density were evaluated by comparing biopsies collected prior to therapy (baseline, N=75 patients) and approximately four weeks after commencing therapy (on-treatment, N=53 patients) from 81 patients; this resulted in a total of 39 paired biopsies after excluding samples that could not be analysed because of absence of tumour cells due to the antitumor immune response had already happened or to insufficient tumour cells in the tissue obtained (Extended Data Figure 2A-C, Supplementary Table 3). Biopsies were reviewed to annotate the tumour bed and periphery to quantitate CD8 positive T cells within the tumour region and along the invasive margin (Extended Data Figure 3A-B). The CD8 T cell density was similar across baseline biopsies between patients who did and did not respond to combination therapy (p=0.58). Following the protocol definition of the assessment of the secondary endpoint, analysing the change in density of CD8 T cells between baseline and on-therapy biopsies from patients in the combination therapy group, there was no significant difference (two-sided α=0.05) in the change in CD8 T cell density between patients who did and did not respond to combination therapy (p=0.77, Figure 4A and Extended Data Figure 3C). Pathological features consistent with the presence of regressed melanoma (defined as tumour necrosis, areas of tumour regression with fibrosis and absence of melanoma cells, or melanosis - which is a pathological description of macrophages that have engulfed pigmented melanoma cells after a tumour regression, according to the analysis of samples after neoadjuvant immunotherapy 22), were observed only in on-therapy biopsies from patients with a clinical CR or PR to combination therapy (11 of 14 patients with CR or PR had features of pathologic regression present, compared to 0 of 18 patients who did not have CR or PR; Fisher’s exact test, p=2.8e-6). The tumour areas with features of pathological regression in the on-therapy biopsies appeared to have low CD8 T cell infiltration and absence of melanoma cells (Figure 4B.

Figure 4. CD8 cell quantitation in biopsy specimens.

Figure 4.

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A) Density of CD8-positive cells detected within the annotated tumour. Paired baseline-on-treatment biopsies are indicated by points connected by lines. Dotted lines indicate patients with observed features of pathological response present in the on-treatment biopsy. The number of patients in each group is indicated by the number along the x-axis (Ipilimumab, N=2 partial response [PR], N=3 stable disease [SD], N=13 progressive disease [PD]; nivolumab and ipilimumab, N=8 complete response [CR], N=9 PR, N=9 SD, N=27 PD). Box plots indicate the median (middle line), 25th and 75th percentiles (box) and 5th and 95th percentiles (whiskers). CD8-positive cell density was compared across biopsies using Wilcoxon rank-sum for two-group comparisons and Wilcoxon signed-rank tests for paired comparisons. B) Representative images of biopsies. Biopsy of a patient with response to nivolumab and ipilimumab with increased CD8 density (left panel); biopsy from a patient with response to nivolumab and ipilimumab and detection of features of pathological regression in the on-treatment biopsy with decrease in CD8 density in that area (middle); and biopsy from a patient with progressive disease following nivolumab and ipilimumab with no change in CD8 cell density (right). Scale bars in each panel are 100um.

Discussion

In this US cooperative group prospective and randomised clinical trial in patients with metastatic melanoma with primary resistance to anti-PD-1-based therapy, the clinical data support the hypothesis that outcomes are improved when introducing CTLA-4 blockade therapy with continuation of anti-PD-1 therapy after progression versus switching to CTLA-4 blockade therapy alone. However, the combination of nivolumab and ipilimumab is associated with a higher rate of grade 3 or higher adverse events, which was consistent with the adverse events previously described for this combination versus for single agent ipilimumab 3. The analysis of baseline and on-therapy changes in CD8 T cell infiltration confirmed that CTLA-4 blockade could result in increases in CD8 T cell infiltration in some cases with primary resistance to PD-1 blockade 5; however the changes in CD8 T cell infiltration observed in the present analysis did not reach statistical significance and thus did not support the formal hypothesis tested as a secondary endpoint of this clinical trial. In some cases, the biopsies showed features of melanoma regression, and in those areas the density of CD8 infiltration decreased suggesting that the biopsy was taken after the peak of the CD8 infiltration induced by blocking CTLA-4 (Extended Data Figure 4) 6–8,10. By adding CTLA4 blockade to continued PD-1 blockade therapy, we hypothesized that T cells (enriched for tumour antigen-specific T cells) would infiltrate metastatic lesions and be able to induce their specific antitumour cytotoxic response by releasing these two major immune checkpoints (Extended Data Figure 5).

In the pivotal Checkmate-067 trial, which tested the combination of nivolumab and ipilimumab in the first line setting in patients with metastatic melanoma, this combination had an absolute increase of 14% in objective response rate as compared to nivolumab alone, but also had a 38% absolute increase in grade 3 or 4 toxicities. Furthermore, no statistically significant OS benefit has been documented between the combination of nivolumab and ipilimumab over nivolumab alone, as studies such as the Checkmate 067 clinical trial were not designed to directly compare outcomes of these two groups 23. Therefore, our study indirectly suggests that it may be reasonable to offer single-agent anti-PD-1 therapy in the first line, limiting the toxicity of the combination with anti-CTLA-4 to patients who progress on single agent therapy. Additionally, patients with BRAF wildtype melanoma have not had highly efficacious second-line therapies since anti-PD-1 therapy became standard in the first-line setting.

We believe that this study has implications for other cancers, as it demonstrates an efficacy benefit with continued PD-1/L1 blockade therapy beyond progression as compared to switching to a new agent altogether. As such, this study serves as a proof-of-concept across tumour types and provides justification for investigators and drug developers to design studies in the second-line or later that include continued PD-1 blockade therapy even when the patient may have already progressed on PD-1 blockade therapy in a prior line. However, each combination will need to be tested individually as there is a potential that the combination of CTLA-4 and PD-1 blockade has synergistic effects that may not be evident with other combinations with PD-1 blocking agents. Our data agree with three previously reported studies in patients with advanced melanoma resistant to anti-PD-1/L1. One study including 19 patients showed similar response rates in patients who received nivolumab and ipilimumab or single agent ipilimumab, and there were increased circulating CD4+ T cells with higher polyfunctionality and higher interferon-gamma production among patients in both groups who achieved disease control 20. Two other studies, one a prospective single-arm study of 70 patients treated with ipilimumab 1mg/kg and the anti-PD-1 agent pembrolizumab 19, the other a retrospective study analysing 355 patients 18, showed that anti-CTLA-4 combined with anti-PD-1 resulted in response rates of 29% and 31%, both in a similar range to the 28% response rate in this study. In the retrospective study, the ipilimumab-alone group had an ORR of 13% based on 162 patients, which was similar to the ORR of 9% among the 23 patients treated with ipilimumab alone in S1616. The present study is the only one of these studies to show benefit in an appropriately powered randomised controlled study, but as a phase 2 study, the confidence intervals around the clinically significant hazard ratio of 0.64 are wide. While on its own the present study cannot confirm the therapeutic benefit of combination of nivolumab and ipilimumab, its consistency with the data from previous research provides robust confirmation of the previously indicated benefit.

There are several limitations to the S1616 study. First, with 92 randomised patients the study was not as large as other practice-changing studies. This was of necessity as the combination of nivolumab and ipilimumab was frequently used as first line therapy by melanoma clinicians in the United States (US), and doctors and patients needed to be willing to randomise to ipilimumab therapy alone in second line when the combination of nivolumab and ipilimumab could be obtained outside of the clinical trial. Although the PFS benefit was seen despite the small sample size, the small size made it difficult to perform meaningful subset analyses.

Second, due to the relatively long period between study conception and completion (~6 years), certain standards and definitions changed during the course of the study, notably the definition of primary resistance and available first-line therapies. Our study defined primary resistance to PD-1 blockade as melanoma that did not progress on anti-PD-1 therapy at any point after receiving that therapy as long as there was no previous response and no intercurrent therapy. A white paper published in 2020 defines primary progression slightly differently and requires disease progression within 12 weeks after last PD-1 dose 24. Additionally, since the completion of enrolment on our study, a new combination therapy in the first-line setting has been approved by the US Food and Drug Administration. The combination of nivolumab and the lymphocyte-activation gene 3 (LAG-3) blocking antibody relatlimab was demonstrated to have improved PFS as compared to nivolumab alone 25, leading some to adopt this as a new first-line therapy for metastatic melanoma. While patients in our study were eligible even if they had received a combination of PD-1 and another therapy (as long as it was not a CTLA-4 inhibitor) prior to enrolment, in practice very few patients received first-line combination therapy, and none of these patients received relatlimab as part of their combination therapy. As such, the utility of combining nivolumab and ipilimumab after progression on the combination of nivolumab and relatlimab remains unknown. While patients were eligible regardless of BRAF mutation status, no intervening BRAF plus MEK inhibitor targeted therapy was allowed between progression on anti-PD1 therapy and enrolment on S1616. At the time the study was developed, no optimal sequencing of BRAF plus MEK inhibitor therapy and immunotherapy had been determined. On S1616, only one patient with a BRAF mutation received BRAF plus MEK inhibitor targeted therapy before receiving any anti-PD1 therapy while others did not receive BRAF inhibitor therapy at all prior to enrolling on the trial. Since S1616 completed enrolment, the DREAMseq clinical trial demonstrated that BRAF plus MEK inhibitor therapy is less efficacious when given prior to immunotherapy in metastatic melanoma 26. However, an additional limitation to our study is that the total number of patients with BRAF mutations is unknown due to lack of data collected prospectively.

Randomisation was performed in an admittedly unusual 3:1 fashion to ensure adequate power for the main translational objective (the first secondary objective) which was designed to assess differences in CD8 T cell infiltration between biopsies of patients with response or no response to therapy in the combination therapy group. This was due to the translational hypothesis that primary anti-PD-1 resistance could be reversed by adding anti-CTLA-4 therapy to continued anti-PD-1 therapy as evidenced by increases in infiltrating CD8 T cells. This secondary objective was considered sufficiently important to randomise the trial in a manner in which this objective could be tested. To do this, we needed to ensure that there would be enough patients in the combination therapy group whose tumours both responded or did not respond to allow for the comparison to be meaningful. While unbalanced randomisation is less common, the reliability of the design and the analysis of the primary endpoint remains unaffected. Unbalanced randomisation is usually not done because it is less efficient, requiring a larger sample size to maintain adequate statistical power. As such, the study required larger population of patients (by approximately 15%) than would have been necessary under 1:1 randomisation. Despite the relatively large number of biopsies prospectively accrued and analysed from patients enrolled in S1616, there was heterogeneity in the CD8 density assessment and we could not assure having the same lesion being biopsied twice, all of which contributed to some cases having evidence of decreased CD8 infiltration due to the melanoma already having regressed and being cleared by a prior antitumor immune response.

In summary, S1616 demonstrates that combined therapy with nivolumab and ipilimumab yields superior PFS and ORR compared to single agent ipilimumab in patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapy. On the basis of these results, the combination of nivolumab and ipilimumab should be considered the preferred regimen over ipilimumab alone for the treatment of patients with advanced melanoma not responding to prior anti-PD-1, though patients and physicians should consider the corresponding increase in toxicity. 27,28.

Methods

Patients

Patients were eligible if they were at least 18 years old with pathologically confirmed melanoma that was either stage IV or unresectable stage III. Patients with mucosal or cutaneous melanoma were eligible, but patients with uveal melanoma were excluded. Patients must have had prior treatment with anti-PD-1 or anti-PD-L1 agents and had documented disease progression either while on these agents or after stopping therapy with these agents without intervening therapy. Patients must not have achieved a confirmed PR or CR to the anti-PD1/L1 agents prior to progression, thereby excluding patients with acquired resistance to anti-PD-1 24,29. Patients were not allowed to have had prior treatment with ipilimumab or other CTLA-4 antibodies. Patients must have had measurable disease using RECIST version 1.1 21. However, if the only measurable disease was cutaneous or subcutaneous, lesions must have been at least 10 mm in greatest dimension and able to be serially recorded using callipers and photographs. Patients may not have had active central nervous system metastases unless they were adequately treated and symptom-free without requiring steroids for 14 days prior to registration, and must have had a Zubrod performance status of 0–2, and adequate hepatic, renal, and hematologic function. Patients were not eligible if they had a history of immune-related pneumonitis or colitis requiring steroid treatment. Patients had to be willing to undergo serial biopsies and submit tissue and blood for the translational medicine objectives. Sex and/or gender were determined by self-report. Patients were enrolled regardless of sex and/or gender. Characteristics of the study population, including sex and age, are displayed in Table 1.

Trial Design and Treatments

In this phase 2 randomised study, patients were randomly assigned using a 3:1 ratio to receive combination therapy with nivolumab 1mg/kg and ipilimumab 3 mg/kg every three weeks for four cycles followed by nivolumab 480 mg every four weeks for up to two years, or to ipilimumab 3mg/kg every three weeks for four cycles. In the combination group, nivolumab was administered intravenously over 30 minutes on day 1 of each cycle and ipilimumab was administered intravenously over 90 minutes starting 30 minutes after the end of the nivolumab infusion on day 1 of the first four cycles. In the ipilimumab alone group, ipilimumab was administered intravenously over 90 minutes on day 1 of the first four cycles only. Tissue and blood biopsies were collected on or prior to day 1 of protocol treatment and on day 28–35 of protocol treatment. If available, archival tissue prior to previous anti-PD-1 therapy was also collected. Treatment on the ipilimumab group was until progression of disease, until development of unacceptable toxicities, or until the completion of four cycles of treatment, whichever was first. Treatment on the nivolumab and ipilimumab group was until progressive disease, development of unacceptable toxicities, or until two years of treatment with nivolumab, whichever was first. Treatment beyond initial progression as defined by investigators using RECIST version 1.1 was permitted if the investigators assessed that the patient was clinically benefiting from the treatment. Dose reductions were not permitted and dose delays due to toxicity were allowed up to 12 weeks and resumption of dose was generally allowed when toxicity resolved to a grade 1 or lower.

Endpoints and Assessments

The primary endpoint was PFS assessed according to RECIST version 1.1 21 by investigator review and defined as the time between the date of randomization until the earliest date of documented disease progression or the date of death from any cause, whichever occurred first. A single interim analysis was performed on a data lock at March 6, 2020 after 43 progression or death events had occurred. The hazard ratio, using ipilimumab as the reference group, was 0.65 (90% CI 0.37–1.14). The protocol called for early termination if the hazard ratio favoured the ipilimumab group so the protocol met the criteria to continue. Secondary endpoints included change in CD8 T cell infiltrate between on-study biopsy samples of patients who responded to combination therapy. Additional secondary endpoints included ORR, OS, and the toxicity profile of patients in each treatment group. Tumour response, according to RECIST version 1.1, was assessed by the treating investigator every 12 weeks until disease progression. ORR was defined as a complete or partial response to therapy following RECIST version 1.1 21. Two secondary endpoints were to assess the marginal prognostic value of baseline CD8 T cell density, and the change in CD8 density in on-therapy biopsies. Adverse events were assessed continuously throughout the trial and for up to 30 days after completion of the trial using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Analysis of CD8 T cell infiltration

Biopsies were processed at each site using standard clinical pathology processing to obtain formalin-fixed paraffin-embedded (FFPE) tissues. The Translational Pathology Core Laboratory (TPCL) at the University of California, Los Angeles (UCLA) performed histological sectioning, haematoxylin and eosin (H&E) or immunohistochemical (IHC) staining, and digital imaging of stained slides. Three sections (5 µm) were cut from each block, and consecutive slides were stained for mouse anti-human S100 (Cell Marque, Cat#: 330M, 1–400, for melanoma cells), mouse anti-human CD8 (Agilent, M7103, 1–100, cytotoxic T cells), and H&E (for histological assessment). Stained slides were imaged at 40X magnification for analysis. IHC and H&E slide images were assessed using QuPath 0.3.0. S100, CD8, and H&E images were sequentially assessed by two dermatopathologists (P.S., L.F.K.) for manual annotation of two types of regions: ‘Tumour’ regions were identified by the presence of tumour cells that displayed melanoma cytology/morphology with nuclear and cytoplasmic S100 protein expression and ‘Periphery regions were denoted by invasive lymphocyte patterns and cells with CD8 expression along the edges of ‘Tumour’ regions. While reviewing each biopsy, the dermatopathologist noted observations related to immune-mediated pathologic response patterns or visible limitations to annotating tumour regions, including tumour necrosis, regression, melanosis, dense immune infiltrate, or pigmentation. ‘Tumour’ and ‘Boundary’ regions were annotated on CD8 stained slides, and CD8 positive cells were identified and quantified within each region using the QuPath Positive cell detection functionality (Supplementary Table 5). CD8 positive cell density was summarized by the “Number of CD8 positive cells per mm2 tissue”. If there were multiple biopsies performed at a given timepoint, the sum of CD8 positive cells across all biopsies was normalized by the sum of the area (in mm2) of annotated regions across all biopsies.

Trial Oversight

Approval for the trial was obtained through the CTEP Central Institutional Review Board. Additionally, each investigator received approval from their respective institutional review board. The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and all patients provided written informed consent before participation. An independent data monitoring committee provided oversight to assess the efficacy and safety of nivolumab and ipilimumab on the trial. The trial was designed by the SWOG Melanoma Committee in conjunction with the NCI and CTEP and was registered on ClinicalTrials.gov (NCT03033576). Data were collected by SWOG and analysed in collaboration with the authors. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. All authors contributed to drafting the manuscript, provided critical review, and gave final approval to submit the manuscript for publication.

Randomization

Patients were randomized using a 3:1 ratio to receive combination therapy with nivolumab and ipilimumab, or to ipilimumab alone. The randomization did not include any stratification factors. Randomization was completed by sites through the SWOG rando-node dynamic balancing algorithm implemented through the NCI’s OPEN registration platform.

Statistical Analysis

The full details of the design are provided in Section 11 of the protocol document. The statistical design assumed exponential PFS with a median of 3.0 months on the ipilimumab group (null hypothesis). The study was powered to detect a change in median PFS to 6.0 months in the combination therapy group (corresponding to an HR of 0.50). A total of 84 patients (63 randomised to combination group and 21 to ipilimumab group) with 78 events (across both groups) would provide 89% power for a one-sided α of 10% using a log-rank test. A single, pre-specified interim futility analysis was scheduled at 41 events with a plan to stop early for futility if the estimated hazard ratio favoured the ipilimumab group. Unequal randomization was necessary to power the secondary objective, comparing CD8 positive expression in patients who respond compared to patients who do not respond in the combination therapy group. Fifty-six patients (corresponding to 90% compliance in tissue submission) would provide 80% power to detect a mean difference of 0.875 standard deviations in CD8 positive expression between patients with and without response in the combination therapy group at the two-sided α = 0.05 level.

All analyses were conducted at the SWOG statistical centre using intent-to-treat analyses among all eligible randomised patients. The Kaplan-Meier method was used to estimate survival outcomes, and log-rank tests were used to evaluate associations with the outcomes. Fisher’s exact test and the Wilcoxon rank-sum test were used to assess differences in categorical and quantitative variables across groups. Data was provided to SWOG from individual sites through iMedidata Rave, then imported from Rave into the SWOG SQL database, and then exported from the SQL database using SAS (version 9.4). Clinical analyses were completed in R (version 4.0.3) and SAS (version 9.4). CD8 positive cell density was compared across biopsies using Wilcoxon rank-sum for two-group comparisons and Wilcoxon signed-rank tests for paired comparisons. CD8 positive cell density metrics were analysed in R (v4.2.0) and summarized using the tidyverse R package (v1.3.2).

Extended Data

Extended Data Figure 1.

Extended Data Figure 1.

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Kaplan-Meier plot of overall survival.

Extended Data Figure 2.

Extended Data Figure 2.

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CONSORT diagram of tumour biopsies assessed for CD8-positive cell quantitation.

Extended Data Figure 3. Semi-automated workflow for CD8-positive cell quantitation in tumour biopsies.

Extended Data Figure 3.

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A) Representative images for manual annotation of tumour and tumour periphery regions. B) Screenshot of cell segmentation, identifying CD8-positive cells (red) and CD8-negative cells (blue), for CD8 cell quantitation.

Extended Data Figure 4. Model for the mechanism of anti-CTLA-4-mediated sensitization of tumours to anti-PD-1.

Extended Data Figure 4.

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Releasing the CTLA-4 checkpoint at the lymph node to promote T-cell trafficking (A to B) and expansion of CD8 T cells by concurrent anti-PD-1 therapy at the tumour site (B to C).

Extended Date Figure 5.

Extended Date Figure 5.

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Model for the mechanism of reversal of tumour resistance to anti-PD-1 with the addition of anti-CTLA-4.

Supplementary Material

S1616 Supplementary

Acknowledgements:

The authors want to acknowledge the participation of patients and their caregivers, the support of the patient advocates Samantha Guild, JD, and Valerie Guild, and the support of Bristol-Myers Squibb in providing investigational agents for the study.

Funding:

SWOG NIH/NCI grants LS1616_R01LDRGAPP01, U10CA180888, U10CA180819, U10CA180821, U10CA18068. Biopsies and their analyses were supported by the Stand Up to Cancer (SU2C) Catalyst-Bristol-Myers Squibb-American Association for Cancer Research (AACR) grant CT06–17. A.R. is funded by NIH/NCI grants P01 CA244118 and R35 CA197633, and the Parker Institute for Cancer Immunotherapy, the Ressler Family Fund, and the support from Ken and Donna Schultz, Todd and Donna Jones, Karen and James Witemyre, Thomas Stutz, and Jonathan Isaacson. K.M.C. was supported by the Cancer Research Institute Postdoctoral Fellowship Program, the V Foundation Gil Nickel Melanoma Research Fellowship, and the Parker Institute for Cancer Immunotherapy and V Foundation Bridge Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Competing Interests

A.V. declares that he has employment by Caris Life Sciences, and consults with George Clinical, West Clinic; Advisory Boards and Steering Committees: Bristol Myers Squibb, Genentech, Mirati Therapeutics; Research Funding: SWOG, Stand Up 2 Cancer, Bristol Myers Squibb, AACR.

J.M. reports none.

K.K. reports clinical trial funding through the institution from Merck.

N.I.K. reports the following: Advisory Board: Bristol Myers-Squibb, Regeneron, Merck, Iovance Biotherapeutics, Genzyme, Novartis, Nektar, Castle Biosciences, Instil Bio, NCCN (via Pfizer); Study Steering Committee: Bristol Myers-Squibb, Nektar, Regeneron, Replimmune; Data Safety Monitoring Board: Astra-Zeneca, Incyte; Common Stock: Bellicum, Asensus Surgical, Amarin Corp.; Research Funding (to Institute): Bristol Myers-Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience, Amgen, Regeneron, Celgene, Replimmune, Modulation Therapeutics.

K.M.C. reports being a shareholder in Geneoscopy LLC, and has received consulting fees from Geneoscopy LLC, PACT Pharma, Tango Therapeutics, Flagship Labs 81 LLC, and the Rare Cancer Research Foundation.

P.S. received research funding, consulted for, and served on advisory board for Castle Biosciences, Inc.

L.F.K. reports none.

F.C. reports that his institution receives research funding for clinical trials. A portion of that funding comes from trials sponsored by Amgen and Replimune and helps cover her salary.

J.A.S. reports the following: Apixagen Consultation; Iovance: Consultation; Necktor: Consultation. Up-to Date: Royalties

A.I. discloses research funding to institution: Checkmate Pharmaceuticals, Dynavax, GSK/Sarah Cannon, Immunocore, Merck, Neon Therapeutics/Sarah Cannon.

A.I.V. reports that she did have an investigator-initiated study supported by Bristol Myers Squibb, but that it closed 2 years ago and understands that it does not qualify as a conflict of interest.

T-G.T. reports institutional funding from BMS, Merck, Roche, Pfizer, Novartis, Regeneron, Astra-Zeneca TGT.

B.C. reported clinical trial support paid to Institution: SWOG, BMS, Macrogenics, Merck, Karyopharm, Infinity, Advenchen, Idera, Xencor, Compugen, Iovance, PACT Pharma, RAPT, Immunocore, IDEAYA, Ascentage, Novartis, Atreca, Replimmune, Instil Bio, Adagene, TriSalus, Xilio; Payment for lecture: Sanofi Genzyme; Advisory Board: Instil Bio, Nektar, Delcath, Novartis, Genentech, IDEAYA, OncoSec, Iovance, Deciphera

D.C.P. reports none.

Y.C. reports BMS RELATIVITY-098 research funding to his institution; Personal financial interest: -BMS melanoma speaker and advisory board; -Pfizer melanoma speaker.

K.M. reports no relevant competing interests.

C.L.B. reports none.

C.A.D. reports no conflicts of interest or any relationships to declare.

D.B.J. has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte.

Z.E. Reports serving on advisory boards: Array, Pfizer, OncoSec, Regeneron, Genentech, Novartis, Natera; Research funding: Novartis, Pfizer, Boehringer-Ingelheim

S.C. reports serving on the Advisory Boards of Bristol Myers Squibb, Novartis, Pfizer and Regeneron.

E.M. reports no conflicts of interest.

C.R.G. reports no conflicts of interest.

I.B.C. reports no conflicts of interest.

A. V-C. Reports no relevant competing interests to disclose

I.P.G. Reports none.

E.S. Reports none.

S.H-L. reports the following: Consulting: Amgen, Genmab, Xencor, Regeneron, Nektar, Astellas, BMS, Merck; Research support: Amgen, Merck; Contracted Research: Pfizer, Plexxikon, Genentech, Neon Therapeutics, Nektar, Astellas, F Star, Xencor, Merck, Vedanta, Kite Pharma, Boehringer, Ingelheim, OncoC4, Dragonfly, BMS, BioAlta.

S.P.P. reports relevant competing interests: Bristol Myers-Squibb – clinical trial support (institution); advisory board; Cardinal Health – advisory board; Castle Biosciences – advisory board; Delcath - advisory board; consultant; Foghorn Therapeutics – clinical trial support (institution); Ideaya - clinical trial support (institution); Immunocore – data safety monitoring board; Immatics - advisory board; InxMed – clinical trial support (institution); Lyvgen Biopharma - clinical trial support (institution); Novartis – clinical trial support (institution); advisory board; consultant; Pfizer - advisory board; Provectus Biopharmaceuticals – clinical trial support; research support (institution); Reata Pharmaceuticals – clinical trial support (institution), data safety monitoring board; Replimmune - advisory board; TriSalus Life Sciences - scientific advisory board; clinical trial support (institution); Seagen - clinical trial support (institution); Syntrix Bio - clinical trial support (institution); Advance Knowledge in Healthcare – consulting.

K.F.G. is an employee and stockholder of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Newark, NJ, USA

S.L.B. reports none.

M.C.W. reports none.

A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb and Merck, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine and Tango, has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio.

Footnotes

Data Availability Statement

All data and code to reproduce the analyses presented here are available upon request from SWOG following SWOG’s data sharing policy and process: https://www.swog.org/sites/default/files/docs/2019-12/Policy43_0.pdf. The protocol (including statistical analysis plan in Section 11 of the protocol) and informed consent are Supplementary Materials.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1616 Supplementary
NIHMS1939923-supplement-S1616_Supplementary.pdf (5.5MB, pdf)

Data Availability Statement

All data and code to reproduce the analyses presented here are available upon request from SWOG following SWOG’s data sharing policy and process: https://www.swog.org/sites/default/files/docs/2019-12/Policy43_0.pdf. The protocol (including statistical analysis plan in Section 11 of the protocol) and informed consent are Supplementary Materials.

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