Evaluation of baseline and on-treatment serum biomarkers to predict immunotherapy response in solid cancers

Lead Investigator: Niklas Klümper, University Hospital Bonn
Title of Proposal Research: Evaluation of baseline and on-treatment serum biomarkers to predict immunotherapy response in solid cancers
Vivli Data Request: 8699
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Melanoma is a type of skin cancer that is characterized by the uncontrolled growth of pigment-producing cells (melanocytes) in the skin. It is a relatively rare cancer, but it is one of the most aggressive and deadly types of skin cancer. The incidence of melanoma varies depending on the population being studied, but in the United States, it is the fifth most common cancer in men and the sixth most common in women, with an estimated incidence of about 87,110 new cases in 2021.

Urothelial cancer, also known as transitional cell carcinoma, is a type of cancer that affects the cells lining the urinary tract, including the bladder, ureters, and part of the kidneys. It is the most common type of bladder cancer, but it can also occur in other parts of the urinary tract. The incidence of urothelial cancer varies depending on the population being studied, but in the United States, it is estimated to affect about 74,000 people each year.

Renal cell carcinoma (RCC) is a type of cancer that affects the cells in the kidneys. It is the most common type of kidney cancer, and it is often associated with smoking and obesity. The incidence of RCC varies depending on the population being studied, but in the United States, it is estimated to affect about 74,000 people each year.

Hepatocellular carcinoma (HCC) is a type of cancer that affects the liver. It is the most common type of liver cancer and is often associated with chronic liver diseases such as cirrhosis, hepatitis B and C, and alcoholic liver disease. The incidence of HCC varies depending on the population being studied, but in the United States, it is estimated to affect about 41,780 people each year.

Immune checkpoint inhibition (ICI) is a type of cancer treatment that uses drugs to block proteins on immune cells called checkpoints. These proteins normally help to regulate the immune system and prevent it from attacking healthy cells, but cancer cells can exploit them to evade the immune system. By blocking these proteins, immune checkpoint inhibitors can help to restore the immune system’s ability to recognize and attack cancer cells. This treatment approach has been shown to be effective in a number of different types of cancer, including melanoma, HCC, urothelial cancer, and renal cell carcinoma.

However, not every patient profits from ICI. Thus, it is important to identify patients who are candidates for this kind of treatment.

Serum protein concentration can be used as a prognostic marker in cancer patients. The concentration of certain proteins in the blood can provide information about the presence, extent, and severity of cancer. High levels of certain proteins, such C-reactive protein (CRP)can indicate a worse prognosis. On the other hand, low levels of proteins such as albumin in patients with advanced cancer can be a sign of malnutrition and poor prognosis.

However, it is important to note that the use of serum protein concentration as a prognostic marker is not always straightforward and should be interpreted in the context of other clinical and laboratory findings. It is also important to recognize that the prognostic value of a particular protein may vary depending on the type and stage of cancer.

The modified Glasgow prognostic score (mGPS) is a score based on two different laboratory parameters (albumin and C reactive protein) that can be measured in any routine blood draw. It has been shown to be able to yield information on prognosis of patients with different cancers, such as UC, NSCLC and RCC. As part of a currently ongoing research project (Vivli ID: 00007164 + ID: 00007797), we demonstrated that the mGPS outperforms the international metastatic RCC database consortium (IMDC) score, the current clinical standard for risk stratification for patients with metastatic kidney cancer prior start of oncological treatment.

We hypothesize that the concentration of standard serum parameters on its own or integrated into a score like the mGPS can be used to risk-stratify patients with solid metastatic cancers on immunotherapy. Solid cancer is a type of cancer in which the cancer cells form a mass or tumor that is solid. This is in contrast to liquid cancers, such as leukemia or other blood cancers, which do not form a solid mass.

Our primary aim is to explore the prognostic value of serum parameters in patients with advanced or metastatic melanoma, HCC, urotheliel carcinoma and renal cell carcinoma treated with immune checkpoint inhibition (ICI). To address this aim, we have identified several clinical trials that have tested the efficacy of immunotherapy with atezolizumab in these types of cancers. In these clinical trials, blood tests of serum proteins (such as CRP, albumin, etc.) were performed as a standard procedure and form the basis for our analyses in correlation to clinical outcomes.

This study will help to more precisely predict an individual patient´s risk by the concentration of standard serum parameters and thereby add an important tool for clinicians to inform the choice of treatment.

Statistical Analysis Plan:

Our primary aim is to explore the prognostic value of serum parameters in patients with advanced or metastatic melanoma, HCC, urotheliel carcinoma and renal cell carcinoma treated with immune checkpoint inhibition (ICI). To address this aim, we have identified several clinical trials that have tested the efficacy of immunotherapy with atezolizumab in these types of cancers. In these clinical trials, blood tests of serum proteins (such as CRP, albumin, etc.) were performed as a standard procedure and form the basis for our analyses. We will analyze each study as a single data set and will not pool studies on different cancer types.

Patients with missing data will be excluded.

The mGPS is determined by assigning one point for an elevated serum C-reactive protein (CRP) concentration of > 10 mg/L and a second point for decreased serum albumin (< 3.5 g/dL) only in patients with elevated CRP. Patients are then stratified into low (mGPS=0), intermediate (mGPS=1), and high risk (mGPS=2).

Fisher’s exact, Mann–Whitney U, and Kruskal–Wallis tests will be applied to perform intergroup comparisons. The progression-free
(PFS) and overall survival (OS), including 95% confidence intervals will be estimated with the Kaplan–Meier method and compared with log-rank tests. To compare mGPS risk groups, baseline patient (age, gender, ethnicity, Karnofsky Index) and tumor-related parameters (e.g. histology, PD-L1 expression, previous surgery) on OS and PFS, univariate and multiple Cox regressions will be conducted. Independent variables will only be included in the multiple regression if the respective effect is significant in the univariate analysis; Forward Wald selection will be applied. Statistical analyses will be performed R-Studio via the vivli research environment as previously performed for Vivli ID: 00007164. All statistical tests will be two-sided, and p-values < 0.05 will be considered significant.

Requested Studies:

A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
Data Contributor: Roche
Study ID: NCT03434379
Sponsor ID: YO40245

A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
Data Contributor: Roche
Study ID: NCT02908672
Sponsor ID: CO39262

A Phase I/III, Randomized, Double-Blind, Placebo-Controlled Study of Carboplatin Plus Etoposide With or Without Atezolizumab (Anti-PD-L1 Antibody) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02763579
Sponsor ID: GO30081

A Phase III, Open-Label, Randomized Study of Atezolizumab (MPDL3280A, Anti-Pd-L1 Antibody) in Combination With Carboplatin or Cisplatin + Pemetrexed Compared With Carboplatin or Cisplatin + Pemetrexed in Patients Who Are Chemotherapy-Naive and Have Stage IV Non-Squamous Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02657434
Sponsor ID: GO29438

A Phase III, Open-Label, Multicenter, Randomized Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Paclitaxel or Atezolizumab in Combination With Carboplatin+Nab-Paclitaxel Versus Carboplatin+Nab-Paclitaxel in Chemotherapy-Naive Patients With Stage IV Squamous Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02367794
Sponsor ID: GO29437

A Phase II, Multicenter, Single-Arm Study OF Atezolizumab In Patients With PD-L1-Positive Locally Advanced Or Metastatic Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02031458
Sponsor ID: GO28754

A Phase III, Open-Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Data Contributor: Roche
Study ID: NCT02420821
Sponsor ID: WO29637

A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure With Platinum-Containing Chemotherapy
Data Contributor: Roche
Study ID: NCT02302807
Sponsor ID: GO29294

A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Data Contributor: Roche
Study ID: NCT02951767
Sponsor ID: GO29293 (Cohort 1)

A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer Data Contributor: Roche
Data Contributor: Roche
Study ID: NCT02108652
Sponsor ID: GO29293 (Cohort 2)

A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Administered as Monotherapy or in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Data Contributor: Roche
Study ID: NCT01984242
Sponsor ID: WO29074

Public Disclosures:

  1. Saal, J., Bald, T., Eckstein, M., Ralser, D.J., Ritter, M., Brossart, P., Grünwald, V., Hölzel, M., Ellinger, J. and Klümper, N., 2023. Integrating On-Treatment Modified Glasgow Prognostic Score and Imaging to Predict Response and Outcomes in Metastatic Renal Cell Carcinoma. JAMA oncology. doi: 10.1016/j.euo.2023.11.005
  2. Klümper, N., Cox, A., Eckstein, M., Kuppe, C., Ritter, M., Brossart, P., Luetkens, J., Hölzel, M., Stein, J. and Saal, J., 2024. High serum sodium predicts immunotherapy response in metastatic renal cell and urothelial carcinoma. European Journal of Cancer, p.114089. Doi: 10.1016/j.ejca.2024.114089