MATISSE
2025-11-24
MATISSE: when response begins to challenge surgery
A Journal Club on ultra-short neoadjuvant nivolumab with or without low-dose ipilimumab in resectable cutaneous squamous cell carcinoma — and on the harder question of what evidence should be enough to adapt, reduce, or potentially omit definitive local therapy.
A sustained multidisciplinary conversation
This Journal Club was part of SoCO’s academic–society–industry partnership series. We were pleased to welcome colleagues from Bristol Myers Squibb into the room for the MATISSE discussion. Their participation added an important industry perspective while preserving the meeting’s independent, evidence-focused format.
Ultra-short neoadjuvant immunotherapy before planned surgery
Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial
Breukers SE, Traets JJH, van Dijk SW, et al. Nature Medicine. 2025;31(12):4055–4064.
doi: 10.1038/s41591-025-03943-w
The paper’s most provocative question was not simply whether neoadjuvant immunotherapy works. It was: when a patient responds deeply and quickly, how much surgery and radiation do they still need?
Two doses, surgery at week 4, and an unexpected natural experiment
MATISSE enrolled 50 patients with resectable stage I–IVa CSCC requiring extensive or potentially disfiguring surgery. Patients were assigned to two doses of nivolumab or two doses of nivolumab plus one low-dose ipilimumab dose before planned standard-of-care surgery in week 4. The trial was randomized but explicitly noncomparative: it was not designed or powered to establish superiority of one immunotherapy arm over the other.
55% versus 80% overall pathologic response
Among the 40 patients who proceeded to surgery, MPR or PPR occurred in 55% with nivolumab and 80% with nivolumab plus ipilimumab. The individual components were MPR 45% and 50%, and PPR 10% and 30%, respectively.
Response carried a strong prognostic signal
Patients achieving MPR or PPR had 100% disease-specific survival at 2 years, irrespective of treatment arm.
Nine patients remained cancer-free without surgery or RT
Ten patients chose not to undergo planned local therapy. Nine ultimately achieved a clinical complete remission after only the neoadjuvant treatment and remained cancer-free at a median follow-up of 34 months.
No apparent surgical penalty from the short course
Grade 3 immune-related toxicity was 12% with nivolumab and 8% with nivolumab plus ipilimumab; no grade 4–5 irAEs were observed, and surgery was not delayed because of immune toxicity.
Important design point: the 10 patients who did not undergo planned surgery were not randomized to treatment omission. Their decision created a clinically fascinating observational cohort, but it does not establish that surgery can safely be omitted in otherwise similar responders.
Could we identify the patients in whom de-escalation is safest?
ΔTLG50% emerged as the most actionable early signal
A decrease in total lesion glycolysis at week 4 identified response with 92% accuracy at the primary tumor and 91% accuracy at the index lymph node. An on-treatment decrease was accompanied by 100% 2-year DSS.
Pathology added information, but imperfectly
A week-4 biopsy showing ≤50% viable tumor identified response with 92% sensitivity, 64% specificity, and 82% accuracy.
Anatomic response was less persuasive
The paper reported poor correlation between MR-RECIST response and pathological response, underscoring the challenge of using size-based imaging alone after immunotherapy.
Interesting signals were not yet individual decision tools
Baseline IFN-γ signature was associated with response, while TMB was not discriminating in the expected direction. The authors concluded that these molecular measures were not sufficiently robust for individual treatment decisions.
What did the room believe before discussing MATISSE?
The pre-Journal Club survey deliberately asked the group to commit before the paper discussion: prior experience with nivolumab plus ipilimumab, preferred neoadjuvant agent, how many doses they would give, whether surgery should always proceed, what findings might justify omission, and what barriers limit dual-checkpoint use.
Had the room used NIVO + IPI preoperatively?
Should surgery be automatic after neoadjuvant therapy?
What minimum response might justify omitting surgery?
Who was in the room?
How many high-risk CSCC patients did respondents see each month?
Prior nivolumab + ipilimumab use
Preferred preoperative systemic therapy
How many doses before surgery?
How many doses are needed for most of the benefit?
Should surgery be automatic after neoadjuvant therapy?
What findings might support omission of surgery?
Minimum response required to consider surgery omission
Where might nivolumab + ipilimumab fit?
Barriers to preoperative nivolumab + ipilimumab
MATISSE pushed beyond response rate
Does ipilimumab add enough to matter?
The numerical difference in total pathological response was provocative, but the study was noncomparative and not powered to establish superiority of NIVO + IPI. The discussion therefore had to separate biological plausibility from causal evidence.
Can a compelling natural experiment become a treatment strategy?
The nine durable clinical complete responses without surgery were difficult to ignore. But patient-selected omission is not the same as prospectively assigned response-adapted de-escalation.
What should be sufficient to change local therapy?
Physical examination, CT/MRI, FDG-PET, and on-treatment biopsy each answer different questions. The meeting focused on which combination could be trusted enough to support a major decision such as omitting surgery.
Benefit is not only recurrence control
The quality-of-life signal in the surgery-omission cohort made treatment burden part of the efficacy discussion: organ preservation, function, and social role matter when evaluating a response-guided strategy.
Who joined us?
| Name | Minutes | Camera | Unmuted | Raised hand |
|---|---|---|---|---|
| Sunandana Chandra | 92 | ● | — | — |
| David M. Miller | 85 | ● | — | — |
| Frances Collichio | 84 | ● | ● | ● |
| Gregory Norigian | 84 | ● | ● | ● |
| Sonia Cohen | 84 | ● | ● | — |
| Cara Trulli | 83 | ● | ● | — |
| Elizabeth I. Buchbinder | 83 | ● | ● | — |
| Ross D. Merkin | 83 | ● | ● | ● |
| Howard L. Kaufman | 82 | ● | ● | — |
| Andrew D. Knight | 81 | ● | ● | — |
| Juliane Andrade Czapla | 80 | ● | — | — |
| Sameer Gupta | 79 | ● | ● | — |
| Jennifer Desimone | 78 | ● | ● | — |
| Vishal Patel | 77 | ● | ● | ● |
| Manisha Thakuria | 76 | — | — | — |
| Ron S. Gejman | 76 | ● | — | — |
| Sasha J Hussain | 76 | ● | — | — |
| Omid Najmi | 75 | ● | ● | — |
| Kevin S. Emerick | 74 | ● | ● | ● |
| Krista M. Rubin | 60 | ● | — | — |
| Ryan J. Sullivan | 59 | ● | ● | — |
| Suzanne Topalian | 59 | — | — | — |
| Christine C. Cimoch | 58 | ● | ● | — |
| Alex Sorrentino | 54 | — | — | — |
| Molly Yancovitz | 48 | — | — | — |
| Meghan J. Mooradian | 42 | — | ● | — |
| Frank Worden | 30 | — | ● | — |
| Mariam El-Ashmawy | 26 | ● | ● | — |
| Ken Tsai | 23 | — | — | — |