PD-1 inhibitor combined with ADC opens up a new direction for the treatment of advanced and metastatic urothelial cancer 2021 CSCO famous doctor Kung Fu tea

*For medical professionals to read only, Professor Sheng Xinan is a guest doctor Kung Fu tea, sharing the progress of urothelial cancer drug treatment.
Urothelial cancer (UC) is one of the malignant tumors of the urinary system.
Its main treatment methods include surgical treatment, drug treatment and Radiotherapy
.

Among them, drug treatment for advanced UC and metastatic urothelial carcinoma (mUC) has a good objective response rate (ORR), but the overall survival (OS) is not long, so it has always been a clinically difficult problem
.

In recent years, with the development of immunotherapy and targeted therapy, the drug treatment of advanced UC and mUC has also undergone major changes
.

The 24th National Conference on Clinical Oncology and 2021 Chinese Society of Clinical Oncology (CSCO) Annual Meeting was held in Beijing
.

At this CSCO annual meeting
.

"Medical Oncology Channel" is fortunate to invite Professor Sheng Xinan to be a guest on the "Famous Doctor Kung Fu Tea" column to share with us the cutting-edge progress and clinical application experience of UC drug treatment
.

Scan the QR code to view the wonderful video.
New advances in drug treatment for advanced UC/mUC.
Clinically, drug treatment for UC is mainly divided into two directions, one is preoperative and postoperative adjuvant therapy, especially neoadjuvant chemotherapy; the other It is chemotherapy for advanced UC/mUC
.

In the past few decades, the traditional first-line treatment program is mainly cisplatin-based systemic therapy, including gemcitabine + cisplatin (GC) regimen, dose-enhanced methotrexate + adriamycin + vincristine + cisplatin Platinum (ddMVAC) programs have certain clinical benefits[1,2], and the objective response rate (ORR) is about 40%, but the 5-year overall survival rate of mUC is still <10%[3]
.

Therefore, new drugs to improve the survival rate of patients are still needed
.

In recent years, immunotherapy and targeted therapy of mUC have developed rapidly, bringing new dawn to patients
.

Immunotherapy drugs based on PD-1 and PD-L1 inhibitors have become the best choice for patients with unsatisfactory chemotherapy effects
.

For people who are more sensitive to immunotherapy, the efficacy of PD-1/PD-L1 inhibitors can last for about two years, and the survival benefit is very significant
.

Unfortunately, nearly half of patients cannot benefit from immunotherapy
.

For these people, FGFR targeted drugs or ADC drugs are also good choices
.

Clinical studies have proved that after receiving the treatment of the FGFR targeted drug erdatinib, the ORR was 40% [4], which basically reached a level similar to that of platinum drugs
.

ADC drugs can accurately locate and kill tumor lesions like a missile.
For example, Vidicuzumab targets the HER2 protein on the tumor surface.
Its antibody has a high affinity for HER2 and can efficiently bind to it and enter cancer cells.
Effectively kill cancer cells
.

ORR is as high as 94.
1%, ADC+PD-1 inhibitor opens a new direction for UC drug therapy? When the ORR of platinum drugs and targeted drugs is mostly at 40% to 50%, is there a new treatment plan that can break through this bottleneck? A clinical trial led by Professor Guo Jun has made good progress.
The trial aims to evaluate the anti-tumor activity and anti-tumor activity of the PD-1 inhibitor teriplizumab combined with the ADC drug RC-48 in patients with locally advanced or mUC Security [5]
.

At the ASCO meeting in April this year, Professor Sheng had already made a phased report.
At that time, 17 patients were enrolled
.

The results of the study showed that in 17 patients who had received at least one efficacy evaluation, the ORR of teriprizumab combined with RC-48 treatment was as high as 94.
1% [5]
.

And 2 patients achieved complete remission (CR)
.

Figure 1 In this clinical trial, two patients have reached CR.
Figure 2 The changes in tumor lesions of patients in this clinical trial.
It can be seen that the degree of reduction is generally higher.
This study further increased the number of patients enrolled
.

At this CSCO conference, Professor Guo Jun’s team reported the data of nearly 30 cases-ORR can still be maintained at 70%~80%
.

Professor Sheng pointed out that after the number of participants in this clinical trial was expanded, the curative effect still reached a relatively ideal level
.

If the treatment population can be expanded, it may benefit more patients
.

At present, this attempt is an exploratory study with certain limitations, and a larger-scale clinical study is needed to further verify its efficacy
.

 How safe is the "target-free" joint program? According to the results of clinical trials, immunotherapy combined with ADC drugs have achieved good curative effects
.

But in terms of safety, will combination drugs increase the risk of adverse events? Professor Sheng mentioned that the current common adverse reactions are mainly fatigue and loss of appetite, which are also accompanied by changes in some laboratory test indicators, such as increased liver function enzyme indicators
.

The abnormal liver function that occurs after using this program may be immunotherapy-related hepatitis
.

In addition, there may be inflammation of multiple organs such as immunotherapy-related pneumonia and enteritis
.

Therefore, clinical trials not only need to verify the efficacy of the combination therapy, but also need to focus on the safety of the drug
.

Only when the safety of the drug is acceptable, can the Phase 2 and Phase 3 clinical trials be continued
.

On the contrary, if the safety of the drug exceeds our controllable range, it means that the combination of the two drugs is not ideal
.

High effective rate and low incidence of adverse reactions is an ideal treatment plan
.

Professor Sheng emphasized: “Although the combination of PD-1 inhibitors and ADC drugs has a good application prospect, the risk of rushing to adopt the combination therapy is very high
.

While considering the efficacy, it is also necessary to fully consider the possible causes of the combination of drugs.
adverse events
.

is not associated with the two methods will be able to achieve even 1 + 1 = 2> 2
.

combination regimen to try in clinical practice, oncologists need thorough evaluation and plenty of experience
.

otherwise, it should be Wait until the clinical trial results to verify its effectiveness and safety before applying it to the clinic
.

When can the "target-free" combination be advanced to the first-line treatment plan? The "target-free" joint program provides new ideas for the diagnosis and treatment of advanced UC and mUC, and its experimental data also give people hope
.

But when can immunotherapy combined with ADC drugs move forward to the first-line treatment of advanced UC and mUC? Professor Sheng emphasized that at present, both PD-1 inhibitors and ADC drugs are still in the second-line treatment plan
.

In the field of first-line treatment, the status of platinum drugs has been unshakable in the past three decades
.

Even if we have entered the age of immunotherapy, emphasizing the combination of immunotherapy and chemotherapy, in the end, it has not shaken the status of platinum-based chemotherapy
.

Therefore, the first-line treatment plan still needs to follow the standard platinum-based chemotherapy
.

As for when ADC drugs or other drugs enter the first-line treatment, randomized controlled clinical trials are required to conduct a one-to-one PK between platinum drugs and ADC
.

If ADC drugs are significantly better than platinum drugs, there may be hope to enter first-line treatment recommendations
.

If the difference between the two treatment options is not significant, platinum-based drugs are still recommended for patients with advanced UC/mUC
.

 What should be explored for UC drug treatment? There are still many unmet needs for the drug treatment of UC
.

Professor Sheng mentioned: "Although the objective remission rate of platinum in the first-line treatment is relatively high, many patients cannot tolerate the adverse reactions of platinum, especially the adverse reactions of the digestive tract
.
It
is research to seek better tolerance.
One of the directions of the author’s exploration
.

More importantly, although the OS of UC has been prolonged with the advancement of drugs, it still has a certain gap compared with other urinary system tumors, such as kidney cancer and prostate cancer
.

Late stage .
The median OS of renal cancer patients is currently close to five years, and advanced prostate cancer is even close to six or seven years
.

However, the median OS of advanced UC or mUC is only about one to two years
.

We also look forward to a significant increase in advanced UC and mUC.
Patients with OS, PFS, drugs with good safety
.

"Expert Profile" Professor Sheng Xinan, Chief Physician, PhD Supervisor, Peking University Cancer Hospital, Deputy Director, Department of Renal Cancer and Melanoma, Chinese Society of Clinical Oncology (CSCO) Council Member, CSCO Youth Expert Committee, CSCO Renal Cancer Expert Committee Secretary, CSCO Urothelial Cancer Expert Committee, Standing Committee, China Executive Director of the Youth Council of the Anti-Cancer Association Member of the Renal Cancer Group of the Urinary Oncology Committee of the Chinese Anti-Cancer Association Deputy Leader of the Oncology Group of the Chinese Medical Association Urology Division Youth Committee, Beijing Anti-Cancer Association Urogenital Tumor Committee Youth Committee Chairman, Beijing Medical Association Oncology Branch Standing Committee Reference: [1] Witjes JA, Lebret T, Comperat EM, et al.
Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer[J].
EuropeanUrology, 2017, 71(3) :462-475.
[2] von der Maase H, Hansen SW, Robert JT, et al.
Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase Ⅲ study[J].
J Clin Oncol, 2000, 18(17):3068-3077.
[3] Roberts JT, von der Maase H, Sengelov L, et al.
Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer[J].
Ann Oncol, 2006,17(Supl 5):118-122[4 ] Necchi A, Siefker-Radtke AO, Loriot Y, et al.
Erdafitinib(ERDA) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC): Subgroup analyses of long-term efficacy outcomes of a pivotal phase Ⅱ trial( BLC2001)[J].
Ann Oncol, 2020, 31(Supl 4):S583-S583[5] Abstract 4534, 2021 ASCO Annual meeting.
Subgroup analyses of long-term efficacy outcomes of a pivotal phase Ⅱ trial(BLC2001)[J].
Ann Oncol, 2020, 31(Supl 4):S583-S583[5] Abstract 4534, 2021 ASCO Annual meeting.
Subgroup analyses of long-term efficacy outcomes of a pivotal phase Ⅱ trial(BLC2001)[J].
Ann Oncol, 2020, 31(Supl 4):S583-S583[5] Abstract 4534, 2021 ASCO Annual meeting.