Science - 31 January 2020

responses (defined as≥30% decrease in the
sum of tumor diameters) were observed in
only 2 of 21 (10%) patients, major pathologic
responses at the primary tumor site (≤10%
viable tumor cells remaining) were seen in 9 of
20 (45%) operable cases. Thus, conventional
radiographic studies underestimated the extent
and rapidity of pathologic responses, which
were characterized by an influx of immune
cells and proliferative fibrosis, which is consist-

ent with an immunological mechanism. The

degree of pathologic response significantly cor-

related with tumor mutational burden and

with the computationally predicted neoantigen

burden. Furthermore, an in-depth study of one

patient revealed that neoantigen-specific T cell

clones that were present intratumorally and in

TDLN expanded in the peripheral blood during

preoperative nivolumab therapy; these clones

persisted in the periphery for weeks after tumor

resection. This example appears to recapitulate

findings from mouse tumor models of neo-

adjuvant immunotherapy described above,

supporting the notion that neoadjuvant im-

munotherapy can amplifysystemicantitumor

immunity and that these effects may persist

even after surgical removal of the primary tumor

and regional lymph nodes. A follow-up analysis

ofTcellclonaldynamicsfromthisstudyshowed

that pathologic response was correlated with

Topalianet al.,Science 367 , eaax0182 (2020) 31 January 2020 4of9

Table 1. Anti–PD-1–based neoadjuvant therapy trials in melanoma.AJCC, American Joint Commission on Cancer ( 10 ). Stage III, regional lymph node

metastases; stage IIIB/C, macroscopic regional lymph node metastases; stage IV, disseminated metastases. ORR, objective response rate (complete + partial

responses) based on radiographic and clinical assessments according to RECIST1.1 ( 83 ). pCR, pathologic complete response; MPR, major pathologic response,

≤10% viable tumor cells remaining; pPR, pathologic partial response,≤50% viable tumor cells remaining. AE, treatment-related adverse event (toxicity).

ClinicalTrials.gov

identifier (citation)

NCT02519322

( 49 )

NCT02437279

( 50 )

NCT02434354

( 51 )

NCT02977052

( 52 )

Phase of trial............................................................................................................................................................................................................................................................................................................................................21b 1b2

Randomization

Monotherapy

versus combination

therapy

Neoadjuvant

versus adjuvant

therapy

Not done

Three different

combination

............................................................................................................................................................................................................................................................................................................................................therapy regimens

Number of

evaluable patients

23 20 29 86*

............................................................................................................................................................................................................................................................................................................................................

AJCC stage............................................................................................................................................................................................................................................................................................................................................III to IV IIIB/C III to IV IIIB/C

Treatment period

Preop 8 to 9 weeks +

postop 6 months

Preop 6 weeks +

postop 6 weeks;

or 12 weeks

postop only

Preop 3 weeks +

postop 1 year

Preop 6 weeks

............................................................................................................................................................................................................................................................................................................................................

Anti–PD-1

............................................................................................................................................................................................................................................................................................................................................monotherapy†

............................................................................................................................................................................................................................................................................................................................................ORR 25% Not done Not provided Not done

............................................................................................................................................................................................................................................................................................................................................Pathologic response‡ 25% pCR 30% = pCR + MPR

............................................................................................................................................................................................................................................................................................................................................Grade≥3 AEs 8% Not provided

Anti-PD-1 + anti-CTLA-4

............................................................................................................................................................................................................................................................................................................................................combination therapy§

............................................................................................................................................................................................................................................................................................................................................ORR 73% 50% Not done^35 – 63%

Pathologic response‡ 45% pCR

78% = pCR +

MPR + pPR

65-80% = pCR +

............................................................................................................................................................................................................................................................................................................................................MPR + pPR

............................................................................................................................................................................................................................................................................................................................................Grade≥3 AEs 73% 90% 20-50%

Risk:benefit

Trial stopped early

because of

safety concerns.

Only 10% of patients

completed therapy,

due to toxicity.

Treatment safe and

moderately effective.

6 weeks nivolumab

3 mg/kg + ipilimumab

1 mg/kg identified

............................................................................................................................................................................................................................................................................................................................................as optimal regimen.

Immunologic correlates

of response

Radiographic response

associated with higher

tumor PD-L1 expression

at baseline, and

higher CD8 T cell

density, lymphoid

gene expression, and

TCR clonality in tumor

at 3 to 4 weeks.

Relapse-free survival

associated with pathologic

response; higher PD-L1,

CD3, B2M, and IFN-g–related

gene expression in baseline

tumor; and greater number of

newly detected tumor-resident

T cell clones in the peripheral

blood at week 6.

Relapse-free survival

associated with pathologic

response; higher expression

of genes reflecting T cell

activation and IFN-gsignaling

in baseline tumor; brisk

TILs with increased exhausted

T cells (EOMEShi, Tbetlo)

and decreased proliferating

Tregcells in tumor at

week 3; and gene

expression reflecting

intratumoral angiogenesis

and B cells.

Relapse-free survival

associated with

pathologic response

and higher IFN-ggene

expression signature

in baseline tumor.

............................................................................................................................................................................................................................................................................................................................................

*An extension cohort of approximately 100 patients who will receive the selected optimal neoadjuvant regimen provides for limited surgery in patients achieving a pCR or MPR on biopsy.

†Anti–PD-1, nivolumab in ( 49 ) and pembrolizumab in ( 51 ). ‡In specimens resected after neoadjuvant therapy. §Anti–PD-1 (nivolumab) plus anti–CTLA-4 (ipilimumab).

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