The Sound of Silence Lights Up the World - Colorectal Cancer ESMO Highlights Review

preface

Although the results of the 2022 European Society for Internal Oncology Annual Meeting (ESMO) in the field of coloral cancer (CRC) treatment, which ended on September 13, are missing large phase III studies, there is no shortage of blockbuster research releases on colorectal cancer hotspots and difficult issues, including the MOUNTAINEER study of dual-drug targeting HER2-positive metastatic coloral cancer (mCRC), and the double-free combination of TKI treatment microsatellite stabilization (MSS) CRC, and NICHE-2 studies
of double-exempt neoadjuvant therapy for early-stage colon cancer.

Recently, during the "Damo Unlimited X Universal Voice" Merck Cancer Academic Week Colorectal Cancer Summit Forum, we specially invited Professor Zhang Suzhan of the Department of Colorectal Cancer of the Second Affiliated Hospital of Zhejiang University School of Medicine, Professor Yuan Ying of the Department of Medical Oncology, and Professor Ding Peirong of the Department of Colorectal Surgery of the Affiliated Cancer Hospital of Sun Yat-sen University to interpret the heavy research
in the field of ESMO rectal cancer for us.

Expert profile

Professor Zhang Suzhan

Chief Physician Doctoral Supervisor

• Director of the Institute of Oncology, Zhejiang University

• Standing Director of Chinese Anti-Cancer Association

• Former chairman of the Colorectal Cancer Professional Committee of the Chinese Anti-Cancer Association

• Former chairman of the Colorectal Cancer Professional Committee of Zhejiang Anti-Cancer Association

• Former Chairman of the CSCO Colorectal Cancer Expert Committee

Double Dragon Ball Play: Tucatenib combined with trastuzumab for HER2-positive mCRC

Professor Zhang Suzhan

Tucatinib is a targeted drug
for the oral HER2 protein.
In April 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases who had previously received at least one anti-HER2 regimen
.

HER2 overexpression occurs in approximately 3% to 5% of patients with mCRC
.
Preliminary analysis of the MOUNTAINEER study, presented at the 2022 ESMO-GI conference, showed that tucatinib in combination with trastuzumab showed antitumor activity and clinically meaningful improvements in progression-free survival and overall survival in patients with HER2-positive mCRC who had previously been ^treated1
.

This year, ESMO updated the results of the analysis of the MOUNTAINEER study with data results from Cohort C (n=30), including that patients who had received tucatinib monotherapy had the option to cross-use tucatinib plus trastuzumab (Queues A and B)2 without a response at week ¹²
.

As of 28 March 2022, 86 patients in the A+B cohort received 1 dose of ≥ study and 30 patients in the C cohort received the study
.
Both tucatinib monotherapy and tucatinib plus trastuzumab are well tolerated after cross-treatment
.
The objective response rate (ORR) for Week 12 of Cohort C was 3.
3% (95% CI, 0.
1, 17.
2) and the disease control rate (DCR) was 80.
0%.

Of the 30 patients, 28 (93.
0%) received TUC+ Tras and the cORR was 17.
9% (95% CI, 6.
1, 36.
9)²
.

At the same time, ESMO also reported patient-reported outcomes (PROs)
in the MOUNTAINEER study.
The study evaluated the quality of life of patients in cohorts B and C using two methods, EORTC QLQ-C30 and EQ-5D-5L, and conducted questionnaires on day 1 of cycle 1 (C1 D1), C1 D8, and C1 D15, and then every D1 of C2-4 and every 3 cycles thereafter until the end of ^treatment3
.

The findings showed that 37 patients in Cohort B and 28 patients in Cohort C received ≥1 dose of study and completed baseline and at least 1 follow-up HRQoL assessment; Throughout the treatment period, patients receiving tucatinib plus trastuzumab maintained a relatively stable health-related quality of life (HRQoL) and showed a consistent trend with those treated with tucatinib ^monotherapy3
.
The above results support this combination regimen as a potentially important treatment option for patients with HER2-positive mCRC and are well tolerated
.

On September 19 of this year, the FDA granted a priority review of the New Drug Application for Tucatinib Plus Trastuzumab Regimen (sNDA) for the treatment of patients with unresectable or mCRC who
have been treated with at least one regimen of HER2.
The results of the study published at ESMO will further optimize the clinical treatment strategy
of CRC patients with special genetic changes.

Expert profile

Professor Yuan Ying

Chief Physician Doctoral Supervisor

• Director of the Department of Medical Oncology, the Second Hospital of Zhejiang University

• Deputy Director of the Key Laboratory of Malignant Tumor Early Warning and Intervention, Ministry of Education

• Executive Deputy Editor-in-Chief and Director of the Editorial Board of the Journal of Practical Oncology

• Vice Chairman of the Family Hereditary Oncology Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Clinical Chemotherapy Committee of Oncology of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Colorator Cancer Professional Committee of the Chinese Anti-Cancer Association and leader of the genetics group

• Director of the Chinese Society of Clinical Oncology (CSCO).
  

• Vice Chairman of the CSCO Colorectal Cancer Expert Committee

• Member of the Standing Committee of the CSCO Gastric Cancer Expert Committee

• Chairman of the Colorectal Tumor Genetics Committee of the Chinese Medical Doctor Association

Aviluzumab challenges MSI-H/dMMR second-line treatment of coloral cancer

Professor Yuan Ying

Based on the KEYNOTE-177 study, pabolizumab was approved for first-line MSI-H/dMMR mCRC therapy and recommended as standard treatment by multiple guidelines
.
The study of MSI-H CRC for second-line treatment is mainly a one-arm study
.

At this conference, the SAMCO-PRODIGE 54 study explored the application of avelumab (avelumab) in the second-line treatment of MSI-H/dMMR mCRC patients, and the results were published as LBA 23 in the Oral Report on Lower Gastrointestinal ^Tumors4
.

This is a multicenter, Phase II clinical trial designed to evaluate the efficacy and safety
of avelumab versus chemotherapy ± targeted therapy as a second-line treatment for this population.
The primary endpoint of the study was progression-free survival (PFS) assessed according to RECIST v1.
1 for the mITT (modified intention-to-treat)
population.
Secondary endpoints included total survival (OS), ORR, duration of response (DOR), and ^{tolerability4}
.

From April 2018 to April 2021, a total of 122 patients were enrolled in the mITT population, of which 61 were enrolled in the control group and the avelumab group
.
At a median follow-up of 33.
3 months, PFS was better in the avelumab group than in the control group (p=0.
025), with PFS rates of 31% vs 19% and 27% vs 9%
in the 12-month and 18-month groups, respectively.
At the same time, ORR and DCR were similar in both groups (ORR: 29.
5% vs 26.
3%, DCR: 70.
5% vs 77.
3%)
.
Treatment-related adverse events (TRAEs) of ≥grade 3 occurred in 31.
7% of patients in the avelumab group compared with 53.
1%⁴
in the control group.

Aviluzumab for RAS Wild-Type CRC: FIRE-6 Matte

Professor Yuan Ying

The FIRE-6 study (AIO KRK-0118, Abstract 424P) explored the efficacy of avelumab (avelumab) combined with FOLFIRI and cetuximab sequential avelumab maintenance therapy in patients with RAS wild-type CRC who had not previously received ^treatment5
.

The patient receives FOLFIRI every two weeks and is treated with cetuximab once a week for 4 cycles according to the standard dosing schedule, followed by the addition of avelumab (10 mg/kg, q2w) and continued treatment for 4 cycles after initiating avelumab monotherapy ^{maintenance therapy5}
.

A total of 57 patients were included in the study, and overall tolerance was good and no new safety signals
were observed.
The ORR was 73.
2%, the DCR was 87.
5%, and the median PFS was 6.
1 months, and the median OS was not reached
.

The results of the study showed that the addition of aviluzumab (avelumab) did not meet the PFS endpoint
predetermined by the protocol.
Thus, in patients with first-line RAS wild-type mCRC, maintenance therapy with aviluzumab (avelumab) after FOLFIRI/cetuximab induction therapy did not effectively delay disease progression
.
There are currently a number of patients in long-term remission that will be further analyzed
.

MSS-type CRC: "Double Exemption + TKI" mode shows antitumor activity

Professor Yuan Ying

The exploration of the post-line immunotherapy strategy of MSS CRC mainly focuses on two aspects, one is to screen the potential beneficiaries of immunotherapy through biomarkers, and the other is to explore immune-based combination therapy options, and the exploration direction is focused on immunocombined chemotherapy/targeted therapy
.

Combining the backline research data of anti-angiogenic drugs plus immunotherapy drugs reported at the ASCO meeting from 2019 to the present, it is found that different anti-angiogenic drugs have different combined efficacy with PD-1 and PD-L1 inhibitors, and some have an effective rate of more than 30%, and some are zero
.
Therefore, the results of Phase II clinical studies are very inconsistent, and the results of Phase III studies are still to be verified
.

Results
of a Phase I clinical trial of regafinil, ipimumumab and navurizumab in the treatment of chemotherapy-resistant MSS-type mCRCs were reported at ESMO this year.
This is also the first research data published on the "double free + TKI" ^model6
.

The study enrolled chemotherapy-resistant MSS mCRC patients
.
The first dose level (DL) includes regofenib (R) 80 mg, QD x 21D, 1 cycle every 4 weeks, while ipimumab (I) 1 mg/kg, Q6W and navurizumab (N) 240 mg, Q2W
.
If the 1st administration is intolerant, a dose reduction (R reduction)
is allowed.
An extended study of 20 patients enrolled at recommended doses to determine safety and explore ^efficacy6
.

Nine patients were enrolled in the safety cohort and DL1 was determined to be the recommended dose level (RDL
).
RDL enrolled 29 patients and 7 patients had liver metastases
.
ORR 36.
4% in patients without liver metastases, with zero ORR with liver metastases; At the median follow-up of 16 months, the median OS was 7 months for mCRC patients with liver metastasis, 14 months for the overall population, and more than 15 months (not reached) for patients without liver ^disease6
.

Expert profile

Professor Ding Peirong

Chief Physician Doctoral Supervisor

• Deputy Director of the Department of Colorectal Disease, Affiliated Cancer Hospital of Sun Yat-sen University, and Director of Huangpu Ward of Colorectal Department

• Outstanding Young Medical Talents of Guangdong Province (First Batch)

• Vice Chairman of the Family Hereditary Oncology Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Youth Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Chairman of the Hereditary Oncology Professional Committee of Guangdong Anti-Cancer Association

• Vice Chairman of Gastroenterology Branch of Guangdong Medical Association

• Vice Chairman of the Colorectal Genetics Committee of the Chinese Medical Doctor Association

• Vice Chairman of the Youth Committee of MDT Professional Committee of the Surgeon Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Youth Committee of the Colorectal Cancer Professional Committee of the Guangdong Anti-Cancer Association

• Visiting Scholar at Memorial Sloan Kettering Cancer Center (MSKCC) in the United States

• Fellow of American College of Surgeons

NICHE-2 Study: Continues to demonstrate the value of neoadjuvant immunotherapy for people with dMMR

Professor Ding Peirong

As a special subgroup, dMMR/MSI-H CRC still has a large unmet need
in clinical treatment.

Previous studies have shown that even in patients with adjuvant chemotherapy and whose disease-free survival (DFS) is similar to that of patients with pMMR, there is still a need to improve prognosis in high-risk (T4 and/or N2) stage III patients with a 3-year risk of recurrence of more than 40%⁷
.

Neoadjuvant immunotherapy has shown better tumor remission in multiple tumor species, and immune checkpoint inhibitors have also made breakthroughs in the CRC field, and a number of neoadjuvant immunotherapy research data are eye-catching
.

The NICHE study is the beginning
of the exploration of neoadjuvant immunotherapy.
In 2018, ESMO reported an NICHE study of early CRC for dMMR and pMMR, using neo-adjuvanumab plus ipimumab, which observed a 60% complete response rate (pCR) rate and a 95% major pathological remission (MPR) rate in dMMR early ^CRC8
.

Follow-up research on the treatment of locally advanced dMMR rectal cancer through neoadjuvant PD-1 monoclonal antibody Dostarlimab, after six months of neoadjuvant therapy, reached 100% clinical complete remission (cCR), so that rectal cancer patients avoided radiotherapy, chemotherapy and surgery, achieved the purpose of protection, and greatly improved the quality of life of ^patients9
.

A real-world study led by us included 19 patients with dMMR/MSI-H rectal cancer who received immunotherapy as radical therapy from six centers in China
.
All patients received complete clinical remission with PD-1 antibody immunotherapy without surgery, radiotherapy, or chemotherapy, and were followed up only as close as
every three months.
After a median follow-up of 17.
1 months, none of the patients developed local recurrence or distant metastases
.
The cohort has a 2-year recurrence rate and an overall survival rate of 100%.

This study further supports the safety and relative long-term efficacy
of dMMR/MSI-H radical immunotherapy for rectal cancer with larger sample sizes and longer follow-up times (17.
1 months vs 6 months).
Therefore, dMMR/MSI-H rectal cancer that has achieved clinical complete remission after immunotherapy can be considered to be exempted from radiotherapy and chemotherapy and surgical treatment to achieve the purpose of organ function preservation and long-term ^cure10
.

This ESMO further publishes the results of the NICHE-2 ^study11
.
In the NICHE-2 study, patients with non-metastatic dMMR CRC were treated with one dose of ipitimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) and underwent surgery 6 weeks after enrollment; The common primary endpoints were safety (ITT, intending to treat population) and 3-year DFS (PP, eligible population); Secondary endpoints include MPR and pCR rates; Pathological remission is defined as 50% residual live tumor (RVT) and MPR as 10% RVT
.
This report provides safety and pathological remission ^data11
.

A total of 112 patients were enrolled in the NICHE-2 study who were treated
.
Grade 3-4 immune-related adverse events were observed in 3 patients (3%), and only 3 patients experienced surgical delay, reaching the primary endpoint
of safety.
In the PP population (n=107), radiological evaluation showed that 89% of patients at baseline had tumor staging in stage III, 77% at high risk stage III, and 64% at stage ^T411
.

PCR
was observed in 72/107 patients (67%).
The median follow-up was 13 months (range, 1-57 months) and none of the patients experienced disease ^recurrence11
.

The NICHE-2 study further confirmed the pathological remission of short-term neoadjuvanum navolumab combined with ipimumab in patients with dMMR CRC in large cohorts
.

The significant short-term efficacy of neoadjuvant immunotherapy in MSI-H populations has been well established, but there are very few
data on whether short-term efficacy translates into long-term survival benefits 。 A study of T4b MSI-H CRC published by our team this year showed that neoadjuvant immunotherapy was effective in reducing the rate of open surgery (P=0.
000) and combined organ resection (P=0.
025), improving pathological complete remission (P=0.
004), and improving disease-free survival (80.
9% and 47.
1% of the 3-year disease-free survival rate of direct surgery, neoadjuvant chemoradiotherapy/chemotherapy and neoadjuvant immunotherapy, respectively).
and 100%, P=0.
0078) ¹²
.

It can be seen that immunotherapy is gradually changing the treatment pattern of coloral cancer; Especially for patient groups such as T4b, the use of immunotherapy in the neoadjuvant phase may become a relatively standard of care for such high-risk recurrence populations
.
But we still have a lot of open questions to answer and resolve
.
Differences in resistance to immunotherapy and between clinical response and pathological response assessment are also worth noting
.

References:

[1] Strickler J, Cercek A, Siena S, et al.
Primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC.
Presented at: ESMO World Congress on Gastrointestinal Cancer，Abstract LBA 2

[2] J.
H.
Strickler et al.
, Additional analyses of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC， 2022 ESMO Abs# LBA27

[3] Wu C et al.
, Tucatinib plus trastuzumab in patients （Pts） with HER2-positive metastatic colorectal Cancer （mCRC）: Patient-reported outcomes （PROs） from ph 2 study MOUNTAINEER, 2022 ESMO, Abs# 361P

[4] Taieb J et al.
,  Avelumab versus standard second-line treatment chemotherapy in metastatic colorectal cancer （mCRC） patients with microsatellite instability （MSI）: the SAMCO-PRODIGE 54 randomised phase II trial.
2022 ESMO, Abs# LBA23

[5] Stintzing S et al.
, Avelumab added to FOLFIRI plus Cetuximab followed by Avelumab maintenance in patients with previously untreated RAS wild-type colorectal cancer – The phase-II FIRE-6 （AIO KRK-0118）, 2022 ESMO, Abs#424P

[6] Fakih M.
G.
  et al.
, A phase I clinical trial of regorafenib, ipilimumab, and nivolumab （RIN） in chemotherapy resistant MSS metastatic colorectal cancer （mCRC）, 2022 ESMO, Abs#320MO

[7] M.
Chalabi, Y.
L.
Verschoor, J.
van den Berg, et al.
 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study.
 Abs#LBA7.
 Annals of Oncology (2022) 33 (suppl_7): S808-S869.
10.
1016/annonc/annonc1089

[8] M Chalabi, LF Fanchi, KK Dijkstra, et al.
Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers[J].
Nature medicine, 2020, 26（Suppl_5）:1-11

[9] Cercek A et al.
, PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer, N Engl J Med 2022; 386:2363-2376

[10] Eur J Cancer.
2022 Oct; 174:176-184.
doi: 10.
1016/j.
ejca.
2022.
07.
016.
Epub 2022 Aug 26.

[11] Chalabi M et al.
, Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study, 2022 ESMO, Abs# LBA7

[12] Han K, et al.
Dis Colon Rectum.
2022 Apr 29.
doi: 10.
1097/DCR.
0000000000002466

Reviewer: Uni

Typography: Uni

Executive: Tourist