Pancreatic cancer double immune + radiotherapy phase 2 trial achieved good results

In this issue of Featured Latest Clinical Oncology Literature, we have compiled for readers the latest research results on high-grade squamous intraepithelial neoplasia of the vulva, pancreatic cancer, rectal cancer, and renal cell carcinoma published in well-known journals
.

Lancet: The results of a randomized controlled trial by Austrian scholars showed that imiquimod in the treatment of vulvar high-grade squamous intraepithelial tumor was non-inferior to surgery and could be considered as a first-line treatment
.

J Clin Oncol: The results of the CheckPAC trial show that nivolumab + ipilimumab + stereotactic radiotherapy has high antitumor activity and good safety in the treatment of refractory metastatic pancreatic cancer
.

The results of the OPRA trial showed that patients with locally advanced rectal cancer who received a full course of neoadjuvant therapy could preserve organs in about half of the patients without affecting survival
.

Lancet Oncol: Quality of life analysis from the CLEAR study showed that patients with advanced renal cell carcinoma who received lenvatinib plus pembrolizumab had similar or better quality of life scores than sunitinib, especially in the time to final disease progression
.

These results, combined with the efficacy and safety data of lenvatinib plus pembrolizumab, support lenvatinib plus pembrolizumab as first-line treatment for advanced renal cell carcinoma
.

01Imiquimod can be used as first-line treatment for high-grade vulvar intraepithelial neoplasia (VIN), which mainly affects young women, and its incidence has continued to increase in recent years
.

≥80% of high-grade VINs are caused by persistent infection with high-risk human papillomavirus (HPV) (primarily HPV 16)
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The disease can be classified as vulvar high-grade squamous intraepithelial neoplasia (vHSIL) or normal VIN
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Both surgical excision and laser vaporization are effective for high-grade vHSIL, but recurrence occurs in up to 50% of patients
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Surgery can cause complications, and can cause psychological distress to the patient
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Local non-surgical treatments that preserve the anatomical structure of the vulva are gradually gaining popularity.
Among them, imiquimod, as a local immunomodulator, can induce the secretion of pro-inflammatory cytokines, regulate local immune responses, and help clear stubborn HPV infections.
Off-label treatment of high-grade vHSIL
.

However, there are no randomized controlled trials of imiquimod versus surgery
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On April 25, 2022, Lancet published online the results of a randomized controlled trial by Austrian scholars [1], showing that imiquimod in the treatment of vHSIL is non-inferior to surgical treatment and can be considered as a first-line treatment
.

This is a randomized, controlled, non-inferiority phase 3 trial of 110 patients with new or recurrent vHSIL who were randomly assigned 1:1 to receive either topical imiquimod (n=56) or surgery (n=54)
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Treatment with imiquimod was continued for at least 16 weeks and continued for patients who did not achieve clinical complete remission at 4 months for a maximum of 6 months
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Patients in the surgical treatment group were selected by the treating physician for surgical resection or ablation
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The primary endpoint was clinical remission at 6 months, and secondary endpoints included clinical remission, HPV status, and patient-reported outcomes, including satisfaction
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Clinical response was evaluable in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study according to the protocol
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37 (80%) of 46 patients in the imiquimod group achieved a clinical complete response compared with 41 (79%) of 52 patients in the surgery group who achieved a clinical complete response after a single surgical intervention, a proportional difference of - 0.
016 (95% CI, -0.
15 to -0.
18; P=0.
0056) (sic), suggesting that imiquimod treatment is noninferior to surgery
.

Aggressive disease was found in 5 patients who underwent one or two surgeries, but no patients with invasive disease were seen in patients who received imiquimod as per protocol
.

There were no significant differences in HPV clearance rates, adverse events, and treatment satisfaction between study groups
.

This is the first randomized controlled trial comparing imiquimod with surgery for HPV-related vHSIL, and the results show that the 6-month response rate of topical imiquimod is non-inferior to surgery, and the 12-month observation found that imiquimod The clinical and histological remission, HPV clearance, and quality of life of the special group were all non-inferior to surgical treatment
.

The main disadvantage of imiquimod treatment is the long treatment period.
For patients who want immediate efficacy and poor treatment compliance, surgical treatment should be the first choice, otherwise imiquimod should be considered as the first-line treatment option for vHSIL
.

02Nivolumab + ipilimumab + stereotactic radiotherapy for refractory metastatic pancreatic cancer has high anti-tumor activity The current response rate of second-line chemotherapy for metastatic pancreatic cancer is only 10%
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Due to the poor immunogenicity of pancreatic cancer, PD-1/PD-L1 or CTLA-4 antibodies are less effective
.

Evidence suggests that radiotherapy may modulate antitumor immune responses by promoting danger signals, leading to T cell aggregation and activation both inside and outside the irradiated tumor
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Combining immune checkpoint inhibitors with radiotherapy may result in better efficacy
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On April 27, 2022, J Clin Oncol published the results of the CheckPAC trial online [2], showing that nivolumab + ipilimumab + stereotactic radiotherapy has high antitumor activity in the treatment of refractory metastatic pancreatic cancer , and the security is good
.

This phase 2 randomized trial included 84 patients with histologically confirmed metastatic pancreatic cancer and randomly assigned 1:1 to receive nivolumab + stereotactic radiotherapy (n=41) or nivolumab + ipilimumab Anti+stereotactic radiotherapy (n=43)
.

The primary endpoint was the clinical benefit rate, defined as the percentage of patients with stable disease, partial response, or complete response
.

Secondary endpoints include safety and overall response rate
.

The clinical benefit rate of patients receiving nivolumab + stereotactic radiotherapy was 17.
1% (8.
0-30.
6), and the rate of nivolumab + ipilimumab + stereotactic radiotherapy was 37.
2% (24.
0-52.
1)
.

Partial response was observed in 1 patient who received nivolumab + stereotactic radiotherapy, which persisted for 4.
6 months
.

Six patients who received nivolumab + ipilimumab + stereotactic radiotherapy achieved partial responses, with a median duration of response of 5.
4 months (4.
2 to not reached)
.

No treatment-related deaths were observed during the trial
.

In the nivolumab + SRT and nivolumab + ipilimumab + SRT groups, 36 (87.
8%) and 32 (74.
4%) patients, respectively, experienced any grade of treatment-related Adverse events, grade 3 or higher treatment-related adverse events occurred in 10 (24.
4%) and 13 (30.
2%) patients, respectively
.

Common grade 3/4 treatment-related adverse events included diarrhea (11.
6%), fatigue (9.
3%), adrenal insufficiency (7%), colitis (4.
7%), arthralgia (4.
7%), myalgia (4.
7%) ) and increased aspartate aminotransferase (4.
7%)
.

Translational studies found that PD-L1 expression levels were not associated with clinical benefit or survival
.

Decreased levels of IL-6, IL-8, and C-reactive protein during treatment were associated with prolonged survival, while patients with ≥40% increases in IL-6, IL-8, and C-reactive protein levels after initiation of treatment had poorer overall survival
.

Stereotactic radiotherapy combined with nivolumab and ipilimumab has good safety and antitumor activity in the treatment of refractory metastatic pancreatic cancer
.

However, the role played by targeted radiotherapy could not be evaluated
.

Future translational research should focus on the mechanism by which nivolumab + ipilimumab + stereotactic radiotherapy enhances antitumor activity
.

03The whole course of neoadjuvant therapy can preserve organs in half of patients with locally advanced rectal cancer.
The standard treatment options for locally advanced rectal cancer are neoadjuvant chemoradiation (CRT), total mesorectal excision (TME) and postoperative adjuvant chemotherapy.
This treatment strategy Although effective, it can cause intestinal, urinary tract, and sexual dysfunction in patients, and some patients require permanent colostomy
.

Observational studies have shown that organ preservation is feasible in patients with pathological complete remission after neoadjuvant therapy, but there is still a lack of information on organ preservation after full-course neoadjuvant therapy
.

On April 28, 2022, J Clin Oncol published the results of the OPRA trial online [3], showing that about half of the patients who received the full course of neoadjuvant therapy compared with the historical control who received neoadjuvant CRT, TME and postoperative adjuvant chemotherapy Organs can be preserved without compromising survival
.

OPRA is a randomized, open-label Phase 2 trial involving 324 patients with locally advanced rectal cancer with clinical stage II (T3-4, N0) or III (any T, N1-2); patients enrolled 1: 1 were randomized to receive induction chemotherapy followed by CRT (n=158) or CRT followed by consolidation chemotherapy (n=166)
.

Re-evaluation after the full course of neoadjuvant therapy, patients who achieved clinicopathological complete remission or near complete remission were treated with a wait-and-see strategy, and patients who did not achieve pathological complete remission received TME
.

The primary endpoint was disease-free survival (DFS)
.

Organ preservation was a key secondary endpoint
.

With a median follow-up of 3 years, the 3-year DFS was 76% (95% CI, 69-84) in the induction chemotherapy followed by CRT group and 76% (95% CI, 69-83) in the CRT followed by consolidation chemotherapy group.
The results were consistent with the 3-year DFS rate (75%) in historical controls
.

Therefore, the study's primary endpoint, DFS, was not improved in patients who received the full course of neoadjuvant therapy and selective wait-and-see treatment compared with the historical control group, which was not met
.

The 3-year TME-free survival rate was 41% (95% CI, 33-50) in the induction chemotherapy followed by CRT group and 53% (95% CI, 45-62) in the CRT followed by consolidation chemotherapy group
.

There were no significant differences between the groups in local recurrence-free survival, distant metastasis-free survival, or overall survival
.

DFS rates were similar between patients who received TME after restaging and those who received TME after tumor recurrence
.

This study suggests that for patients with locally advanced rectal cancer, the choice of wait-and-see or TEM according to the tumor remission after the whole course of neoadjuvant therapy can preserve the organs of about half of the patients, and has no significant effect on the prognosis of the tumor
.

Although the sequence of CRT and systemic chemotherapy did not affect DFS, organ preservation appeared to be higher with CRT before systemic chemotherapy
.

04Lenvatinib combined with pembrolizumab should be used as first-line treatment for advanced renal cell carcinoma The results of the CLEAR study showed that in patients with advanced renal cell carcinoma, compared with the standard treatment regimen of sunitinib, lenvatinib + palbociclib Progression-free survival was significantly longer in both the bolizumab and lenvatinib+everolimus groups than in the sunitinib group
.

Overall survival was also significantly longer in the lenvatinib + pembrolizumab group than in the sunitinib group
.

However, the effect of lenvatinib plus everolimus on overall survival was not significantly greater than that of sunitinib
.

2 Patients with renal cell carcinoma often have associated signs and symptoms, including flank pain, hematuria, bone pain, cough, palpable renal masses, and paraneoplastic syndromes, which can affect their quality of life
.

In addition, several common adverse events associated with kinase inhibitors and immunotherapy negatively impact quality of life, including rash, nausea, diarrhea, fatigue, and musculoskeletal pain
.

Adverse events can cause patients to temporarily or permanently discontinue treatment, or reduce the dose of the drug, so as to affect the efficacy
.

Therefore, it is extremely important to determine the impact of treatment on health-related quality of life (HRQOL) to optimize patient well-being and outcomes during treatment
.

On April 27, 2022, Lancet Oncol published the HRQOL results of the CLEAR study online [4], showing that the HRQOL score of the lenvatinib + pembrolizumab group was similar to or better than that of the sunitinib group, especially in the final Time to disease progression
.

These results, combined with the efficacy and safety data of lenvatinib plus pembrolizumab, support lenvatinib plus pembrolizumab as first-line treatment for advanced renal cell carcinoma
.

CLEAR is a multicenter randomized controlled phase 3 trial of 1069 treatment-naïve patients with advanced renal cell carcinoma, 355 assigned to lenvatinib + pembrolizumab and 357 assigned to lenvatinib In the tinib + everolimus group, 357 were assigned to the sunitinib group
.

The primary endpoint has been reported
.

The secondary endpoint HRQOL was assessed using three scales: FKSI-DRS, EORTC QLQ-C30 and EQ-5D-3L
.

Due to the outstanding efficacy and safety of the lenvatinib + pembrolizumab group, the researchers focused on analyzing the HRQOL of the lenvatinib + pembrolizumab group and the sunitinib group
.

The median follow-up for the HRQOL analysis was 12.
9 months, and all HRQOL instrument and scale scores were similar across the three treatment groups at baseline
.

At mean follow-up (46 weeks, cycle 15), the least squares mean change in FKSI-DRS was -1.
75 in the lenvatinib + pembrolizumab versus sunitinib arm, respectively (SE, 0.
59) vs.
-2.
19 (0.
66), EORTC QLQ-C30 GHS/QOL change -5.
93 (0.
86) vs.
-6.
73 (0.
94), EQ-5D visual analogue scale -4.
96 (0.
85) vs.
-6.
64 (0.
94) )
.

On the EORTC QLQ-C30 four-item scale, the lenvatinib plus pembrolizumab group was significantly better than the sunitinib group: physical function, fatigue, dyspnea, and constipation, but no advantage on the other scales
.

The sunitinib group did not have an advantage on any scale compared with lenvatinib plus pembrolizumab
.

Analysis of time to first exacerbation showed similar results on most instruments in the lenvatinib plus pembrolizumab and sunitinib groups
.

The median time to first exacerbation of FKSI-DRS was 9.
14 weeks (95% CI, 6.
43-12.
14) in the lenvatinib plus pembrolizumab group compared with the sunitinib group, and in the sunitinib group.
was 12.
14 weeks (9.
14-15.
29; HR, 1.
13; 95% CI, 0.
94-1.
35; P=0.
20); the EORTC QLQ-C30 GHS/QOL scale was 12.
00 weeks (7.
29-15.
14) vs.
9.
14 weeks (6.
29-14), respectively 12.
14; HR, 0.
88; P=0.
17); EQ-5D VAS scale, 9.
43 weeks (6.
43-12.
29) vs.
9.
14 weeks (6.
29-12.
00; HR, 0.
83; P=0-041)
.

The lenvatinib + pembrolizumab group outperformed the sunitinib group on the following items: time to first deterioration in EORTC QLQ-C30 physical function (median 15.
29 weeks vs.
12.
71 weeks; HR, 0.
81; P =0.
034), EORTC QLQ-C30 dyspnea (39.
29 weeks vs.
21.
14 weeks; HR, 0.
79; P=0.
023), EORTC QLQ-C30 loss of appetite (18.
29 weeks vs.
9.
14 weeks; HR, 0.
82; P=0-028 ) and the EQ-5D-3L VAS
.

There were no significant differences in other scale scores
.

Time to final exacerbation was better in the lenvatinib plus pembrolizumab group than in the sunitinib group on nearly all assessment scales
.

Median time to final exacerbation of FKSI-DRS was 134.
14 weeks (95% CI, 120.
00 ~ not estimable) in the lenvatinib + pembrolizumab group compared with the sunitinib group, and The group was 117.
43 weeks (90.
14-131.
29), HR was 0.
70 (95% CI, 0.
53-0.
92; P=0.
0081); EORTC QLQ-C30 GHS/QOL was 114.
29 weeks (102.
14-153.
29) vs.
75.
14 weeks (57.
29-14), respectively 105.
14; HR, 0.
60; P<0-0001); EQ-5D VAS were 124.
86 weeks (94.
71-134.
57) vs.
74.
86 weeks (54.
14-96.
00; HR, 0.
67; P=0.
0012), respectively
.

This study demonstrated that HRQOL scores in the lenvatinib + pembrolizumab group were similar to or better than those in the sunitinib group, especially in time to final disease progression
.

Combined with the efficacy and safety data of lenvatinib + pembrolizumab, the quality of life score in this study supports lenvatinib + pembrolizumab as first-line treatment for advanced renal cell carcinoma
.

Reference 1.
Trutnovsky G, Reich O, Joura EA, et al.
Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial.
Lancet 2022 Apr 25.
DOI:10.
1016/S0140-6736 (22)00469-X (Epub ahead of print).
2.
Chen IM, Johansen JS, Theile S, et al.
Randomized phase II study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer (CheckPAC) .
J Clin Oncol 2022 Apr 27.
DOI: 10.
1200/JCO.
21.
02511 (Epub ahead of print).
3.
Garcia-Aguilar J, Patil S, Gollub MJ, et al.
Organ reservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy .
J Clin Oncol 2022 Apr 28.
DOI: 10.
1200/JCO.
22.
00032 (Epub ahead of print).
4.
Motzer R, Porta C, Alekseev B, et al.
Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study.
Lancet Oncol 2022 Apr 27.
DOI:10.
1016/S1470-2045( 22) 00212-1 (Epub ahead of print).
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