Discovery of new independent prognostic marker for triple-negative breast cancer Weekly Oncology

In this issue of "The Latest Clinical Oncology Literature Selection", we have compiled the latest research results on melanoma, breast cancer, angiosarcoma, esophageal cancer, etc.
published in well-known journals for our readers
.

Lancet: The KEYNOTE-716 study, the world's first Phase 3 trial evaluating adjuvant therapy for stage IIB and IIC melanoma after surgery, showed that adjuvant pembrolizumab significantly reduced the risk of disease recurrence or death compared with placebo , and the security is controllable
.

J Clin Oncol: Studies using the Dutch Cancer Registry show that interstitial infiltrating lymphocytes (sTILs) are an independent prognostic marker for triple-negative breast cancer (TNBC), and that young, node-negative TNBC patients with a high proportion of sTILs have good long-term outcomes
.

JAMA Oncol: The TAPPAS study, the world's first randomized controlled phase 3 trial in patients with angiosarcoma, showed that the combination of carotuximab and pazopanib was not superior to progression-free survival and overall survival pazopanib monotherapy
.

Clin Cancer Res: The ATTRACTION-3 study demonstrated that second-line nivolumab showed clinically meaningful improvements in long-term survival compared with chemotherapy in previously treated patients with advanced esophageal squamous cell carcinoma, and nivolumab was well tolerated Sex is good
.

01 Pembrolizumab adjuvant therapy for melanoma significantly reduces the risk of disease recurrence or death.
Patients with stage IIB and IIC melanoma have a high risk of postoperative recurrence and poor prognosis
.

Surgical treatment is routinely recommended in current guidelines, and there is no effective adjuvant therapy
.

Previous studies have demonstrated that pembrolizumab can prolong progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma, and prolong recurrence-free survival (RFS) in patients with stage III melanoma after resection
.

On March 31, 2022, Lancet published the KEYNOTE-716 study online, which evaluated the efficacy and safety of pembrolizumab as adjuvant therapy in patients with high-risk stage II melanoma after complete resection
.

The results showed that adjuvant pembrolizumab significantly reduced the risk of disease recurrence or death compared with placebo, with manageable safety
.

KEYNOTE-716 is an international multicenter, randomized, double-blind, controlled phase 3 trial of pembrolizumab versus placebo in the treatment of stage IIB or IIC melanoma following complete resection
.

Enrolled patients were 12 years of age and older with newly diagnosed stage IIB or IIC melanoma after complete resection and were randomly assigned 1:1 to pembrolizumab or placebo
.

The pembrolizumab group received pembrolizumab 200 mg (2 mg/kg in pediatric patients) every 3 weeks for 17 cycles (ie, a maximum treatment duration of 1 year)
.

The primary endpoint was investigator-assessed RFS, and secondary endpoints included distant metastasis-free survival, OS, safety, and tolerability
.

From September 23, 2018 to November 4, 2020, a total of 1182 patients were screened, 976 were enrolled and randomly assigned to pembrolizumab (n=487) or placebo (n=489 )
.

The median patient age was 61 years (interquartile range, 52-69), 387 (40%) were female and 589 (60%) were male
.

Of the 976 patients, 874 (90%) were Caucasian and 799 (90%) were non-Hispanic or Latino
.

483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 patients in the placebo group received the prescribed therapy
.

At the time of the first interim analysis (data cutoff date 4 December 2020), median follow-up was 14.
4 months (interquartile range, 10.
2 to 18.
7) in the pembrolizumab group and 14.
3 months in the placebo group months (interquartile range, 10.
1 to 18.
7)
.

Of 487 patients in the pembrolizumab group, 54 patients (11%) had a first relapse or death; of 489 patients in the placebo group, 82 patients (17%) had a first relapse or death (hazard ratio [ HR], 0.
65; 95% CI, 0.
46-0.
92; P=0.
0066)
.

At the second interim analysis (data cutoff date of June 21, 2021), median follow-up was 20.
9 months (interquartile range, 16.
6 to 25.
3) in the pembrolizumab group and 20.
9 in the placebo group months (interquartile range, 16.
7-25.
3)
.

First recurrence or metastasis occurred in 72 patients (15%) in the pembrolizumab group and 115 (24%) in the placebo group (HR, 0.
61; 95% CI, 0.
45-0.
82)
.

Neither group achieved a median RFS at either assessment time point
.

Regarding safety, at the first interim analysis, 78 of 483 patients (16%) in the pembrolizumab group had grade 3-4 treatment-related adverse events
.

the placebo group
.

At the first interim analysis, 4 patients had died from adverse events, all in the placebo group (1 each for pneumonia, COVID-19-related pneumonia, suicide, and tumor recurrence)
.

At the second interim analysis, one additional patient in the pembrolizumab group died from an adverse event (COVID-19-related pneumonia)
.

No deaths due to study treatment occurred in this trial
.

Taken together, the KEYNOTE-716 study, the world's first Phase 3 trial evaluating adjuvant therapy for stage IIB and IIC melanoma after surgery, showed that adjuvant pembrolizumab significantly reduced disease recurrence or death compared with placebo risk, and safety is controllable
.

02 A high proportion of interstitial infiltrating lymphocytes suggests a good long-term prognosis in young patients with lymph node-negative triple-negative breast cancer.
Triple-negative breast cancer (TNBC) refers to estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptors Body 2 (HER2) negative breast cancer
.

Younger patients (<40 years old) are diagnosed with triple-negative breast cancer at a higher rate than older patients
.

TNBC is highly heterogeneous, and both estrogen therapy and targeted therapy respond poorly
.

Although chemotherapy improves survival, it induces age-related acute and chronic side effects, such as premature ovarian failure and cognitive impairment, in most patients with early-stage TNBC.
Develop better treatment strategies for triple-negative breast cancer patients, especially younger patients
.

On March 30, 2022, J Clin Oncol published online a study using the Netherlands Cancer Registry to evaluate the prognostic value of stromal infiltrating lymphocytes (sTIL) in young, node-negative TNBC patients not receiving adjuvant or neoadjuvant chemotherapy
.

The results showed that a high proportion of sTIL indicated a better long-term prognosis, and the proportion of sTIL could be used as an independent prognostic factor
.

The study included 441 young (<40 years old) TNBC patients diagnosed with node-negative (N0) from 1989 to 2000.
None of the patients had received adjuvant or neoadjuvant chemotherapy.
The last follow-up date was June 1, 2014.
day
.

The investigators resectioned and analyzed tumor characteristics of tissue samples from all patients, and a dedicated pathologist assessed the proportion of sTIL in patients, who were divided into three categories: low (<30%), moderate (30%-75%) ) and high (≥75%)
.

Multivariate Cox regression analysis was performed, using the second primary tumor incidence as a competing risk factor, and a competing risk model was used to analyze the cumulative incidence of distant metastases or death
.

The primary endpoint was OS
.

The secondary endpoint was distant metastasis-free survival (DMFS)
.

The median age of patients was 35 years, 49.
4% of patients had tumor stage T1c, 85.
9% of patients had histological grade 3, and 66.
4% of patients received breast-conserving surgery and radiotherapy for breast cancer
.

Genetic testing was available for 380 patients, of whom 27.
1% had BRCA1 mutations
.

There was no significant difference in clinicopathological features between BRCA1 mutant and wild-type patients
.

Among 441 patients, the median sTIL rate was 20%, with half of the patients having a low sTIL rate (<30%), 27% having a moderate sTIL rate (30%-75%), and 21% having a high sTIL rate (≥ 30%).
75%)
.

Increased proportion of sTIL was associated with tumor grade 3, but not with tumor T stage, histological subtype, age, or tumor BRCA1 mutation status
.

In patients with a high proportion of sTIL, the 15-year cumulative distant metastasis or mortality rate was only 2.
1% (95% CI, 0-5.
0); while the patients with a low proportion had a poor prognosis, with a 15-year cumulative distant metastasis or mortality rate of 38.
4% % (95% CI, 32.
1 to 44.
6)
.

The 10-year cumulative second primary tumor incidence was 16.
0% (95% CI, 8.
5-20.
4) in patients with a high proportion of sTILs and 9.
7% (95% CI 5.
8-13.
6) in patients with a low proportion
.

Among patients with BRCA1 mutations, patients with a high proportion of sTIL had a better prognosis (10-year OS, 88.
9%; 95% CI, 77.
8-100) than those with a low proportion (10-year OS, 46.
2%; 95% CI, 34.
4-100).
61.
9,)
.

In addition, each 10% increase in sTIL proportion was associated with a 19% lower risk of death (adjusted HR, 0.
81; 95% CI, 0.
76-0.
87)
.

In conclusion, this study shows that young, node-negative TNBC patients with a high sTIL ratio have a good long-term prognosis, and the sTIL ratio can be used as an independent prognostic factor for future prospective clinical trials on neoadjuvant chemotherapy or adjuvant chemotherapy de-escalation strategies
.

03 Pazopanib plus carotuximab did not improve progression-free survival in patients with advanced angiosarcoma.
Angiosarcoma is a rare, highly aggressive tumor that accounts for approximately 3% of soft tissue sarcomas
.

Advanced-stage patients have limited treatment options, short disease control times, and poor prognosis
.

Pazopanib is an angiogenesis inhibitor that acts on the vascular endothelial growth factor receptor (VEGFR)
.

Preclinical data suggest that targeting both the endothelin and VEGF pathways may inhibit angiogenesis more effectively
.

Carotuximab (TRC105) is an IgG1 antibody that highly binds to endothelin and inhibits signaling
.

In a Phase 1/2 clinical trial, pazopanib-naïve patients with chemotherapy-refractory angiosarcoma received carotuximab plus pazopanib with a median PFS of 7.
8 months
.

Therefore, it is clinically necessary to confirm whether pazopanib combined with carotuximab can improve the PFS of patients with advanced angiosarcoma compared with pazopanib monotherapy
.

On March 31, 2022, JAMA Oncol published the Phase 3 TAPPAS trial online, comparing the efficacy and safety of carotuximab combined with pazopanib versus pazopanib monotherapy in patients with advanced angiosarcoma
.

The results showed that pazopanib combined with carotuximab did not improve PFS in patients with advanced angiosarcoma compared with pazopanib monotherapy
.

The TAPPAS study is a multi-country, multi-center, open-label, parallel-group, phase 3 randomized trial
.

From February 16, 2017, to April 12, 2019, a total of 128 patients from 31 centers in the United States and the European Union participated in the study, and 123 patients were included in the interim analysis
.

The enrolled patients had received ≤2 lines of systemic therapy in the past
.

After enrollment, patients were randomly assigned to standard-dose pazopanib group (oral pazopanib, 800 mg/d) or carotuximab combined with standard-dose pazopanib group (intravenous injection) in a 1:1 ratio.
Carotuximab 10 mg/kg weekly, concurrently with oral pazopanib 800 mg/d)
.

The primary endpoint was PFS, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
1, with blinded independent review of imaging and skin photographs
.

Secondary endpoints included objective response rate (ORR) and OS
.

Of the 114 evaluable patients (53 in the pazopanib group and 61 in the combination group), 69 (60%) were women, the median age was 68 years (range, 24-82 years), and 57 were women.
(50%) had skin disease, and 32 (28%) had no prior treatment
.

Data cutoff date is March 14, 2019
.

Median follow-up for OS was 4.
6 years (range, >1 month to 23 months)
.

Median PFS was 4.
3 months (95% CI, 2.
9 to not reached) in the pazopanib group and 4.
2 months (95% CI, 2.
8 to 8.
3) in the combination therapy group
.

The primary endpoint (PFS) was not met (HR, 0.
98; 95% CI, 0.
52-1.
84; P=0.
95)
.

OS was 7.
7 months (95% CI, 6.
8 to not reached) in the zopanib arm and 10.
9 months (95% CI, 6.
8 to not reached) in the combination arm (HR, 0.
79; 95% CI, 0.
41 to 1.
51) ; P=0.
47)
.

The ORR was 13% (95% CI, 6%-24%) in the blinded independent review arm with pazopanib and 5% (95% CI, 1%-14%) in the combination arm (P=0.
09) for pazopanib The most common all-grade adverse events in the panib monotherapy group compared with the combination therapy group were fatigue (29 [55%] vs.
37 [61%]), headache (12 [23%] vs.
39 [64%]), diarrhea (27 [51%] vs.
35 [57%]), nausea (26 [49%] vs.
29 [48%]), vomiting (12 [23%]) ] vs.
23 [38%]), anemia (5 [9%] vs.
27 [44%]), epistaxis (2 [4%] vs.
34 [56%]), and hypertension (29 [55%] vs.
22 [36%])
.

Three patients (6%) in the pazopanib group died within 30 days of the end of the trial treatment (1 from multiple organ failure, 1 from liver failure, and 1 from sepsis) compared with the combination therapy Five patients (8%) in the group died (3 from disease progression and 2 from respiratory failure)
.

In conclusion, the TAPPAS study is the world's first randomized controlled phase 3 trial in patients with angiosarcoma.
The results show that the PFS and OS of carotuximab combined with pazopanib are not better than those of pazopanib alone.
drug treatment
.

Given the high biological heterogeneity of angiosarcoma, follow-up efforts should focus on the development of specific biomarkers for systemic treatment of angiosarcoma
.

04 Long-term follow-up results of nivolumab in the second-line treatment of advanced esophageal squamous cell carcinoma show improved overall survival Nivolumab is a programmed death receptor-1 (PD-1) immune checkpoint inhibition.
Nivolumab treatment showed a survival benefit regardless of the expression level of death receptor ligand-1 (PD-L1)
.

At a median follow-up of 17.
6 months, the median OS was 10.
9 months, compared with only 8.
4 months for chemotherapy patients
.

Based on this, nivolumab has been approved by Japan, South Korea, the United States, China and other countries as a second-line treatment for patients with unresectable advanced or recurrent or metastatic esophageal squamous cell carcinoma
.

There are limited follow-up data on long-term survival of patients with advanced esophageal squamous cell carcinoma using immune checkpoint inhibitors
.

On March 30, 2022, Clin Cancer Res published online 3-year follow-up data from the ATTRACTION-3 study of second-line nivolumab in the treatment of advanced esophageal squamous cell carcinoma
.

The results of the study showed that the OS of the nivolumab group continued to improve compared with the chemotherapy group, and the safety follow-up showed that nivolumab was well tolerated
.

ATTRACTION-3 is a multicenter, randomized, open-label Phase 3 trial
.

From January 7, 2016, to May 25, 2017, the study screened a total of 590 patients, of which 419 patients were enrolled and randomly assigned 1:1 to nivolumab or chemotherapy
.

There were 210 patients in the nivolumab group (240 mg nivolumab intravenously, once every 2 weeks, every 6 weeks as a cycle), and 209 patients in the chemotherapy group (chemotherapy regimen selected by the investigator: paclitaxel every Weekly intravenous administration of 100 mg/m2 for 6 weeks, 1 week off, every 7 weeks as a cycle; or docetaxel 75 mg/m2 intravenously, every 3 weeks, every 3 weeks as a cycle)
.

The primary endpoint was OS
.

Secondary endpoints included ORR, best overall response rate (BOR), disease control rate (DCR), PFS, duration of response (DOR), and safety
.

The data cutoff was May 25, 2020, and the minimum follow-up period was 36.
0 months
.

The median OS was 10.
9 months (95% CI, 9.
2-13.
3) in the nivolumab group and 8.
5 months (95% CI, 7.
3-9.
9) in the chemotherapy group, with a significant risk of death in the nivolumab group lower than the chemotherapy group (HR, 0.
79; 95% CI, 0.
64-0.
97; P=0.
0264)
.

Compared with chemotherapy, OS was better in the nivolumab group at 1 year (46.
9% vs.
34.
7%), 2 years (20.
2% vs.
13.
5%), and 3 years (15.
3% vs.
8.
7%).
high
.

The median PFS was 1.
7 (95% CI, 1.
5-2.
7) and 3.
4 (95% CI, 3.
0-4.
2) months in the nivolumab group and chemotherapy group, respectively, and the HR was 1.
07 (95% CI, 1.
07).
0.
87-1.
33)
.

Compared with the chemotherapy group, the nivolumab group had higher PFS at 1 year (11.
9% vs.
7.
2%), 2 years (5.
4% vs.
2.
4%), and 3 years (4.
3% vs.
1.
6%)
.

Median OS was 19.
9 and 15.
4 months for patients with complete/partial response, stable disease, and progressive disease in the nivolumab and chemotherapy groups, respectively (HR [95% CI], 0.
84 [0.
46-1.
54]) , 17.
4 and 8.
8 months (HR [95% CI], 0.
41 [0.
23-0.
71]) and 7.
6 and 4.
2 months (HR [95% CI], 0.
59 [0.
39-0.
88])
.

Regarding safety, 138 (66.
0%) patients in the nivolumab group reported treatment-related adverse events of any grade, compared with 198 (95.
2%) in the chemotherapy group, and 40 (19.
1%) and 133 in the chemotherapy group, respectively.
Treatment-related adverse events of grade 3 or higher occurred in 63.
9% of patients
.

In conclusion, the ATTRACTION-3 study demonstrated that in previously treated patients with advanced esophageal squamous cell carcinoma, second-line nivolumab showed a clinically meaningful improvement in long-term OS compared with chemotherapy
.

Safety follow-up showed that nivolumab was well tolerated
.

Reference 1.
Luke JJ, Rutkowski P, Queirolo P, et al.
Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.
Lancet 2022 Mar 31.
DOI: 10.
1016/S0140-6736(22)00562-1 (Epub ahead of print).
2.
de Jong VMT, Wang Y, ter Hoeve ND, et al.
Prognostic value of stromal tumor-infiltrating lymphocytes in young, node -negative, triple-negative breast cancer patients who did not receive (neo)adjuvant systemic therapy.
J Clin Oncol 2022 Mar 30.
DOI: 10.
1200/JCO.
21.
01536 (Epub ahead of print).
3.
Jones RL, Ravi V, Brohl AS, et al.
Efficacy and safety of TRC105 plus pazopanib vs pazopanib alone for treatment of patients with advanced angiosarcoma A randomized clinical trial.
JAMA Oncol 2022 Mar 31.
DOI:10.
1001/jamaoncol.
2021.
3547 (Epub ahead of print).
4.
Okada M, Kato K,Cho BC, et al.
Three-Year follow-up and response–survival relationship of nivolumab in previously treated patients with advanced esophageal squamous cell carcinoma (ATTRACTION-3).
Clin Cancer Res 2022 Mar 16.
DOI:10.
1158/1078-0432.
CCR-21-0985 (Epub ahead of print).
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