Editor's Note: Previous studies have demonstrated that short-term efficacy metrics, such as objective response rate (ORR), are associated with long-term survival outcomes, such as overall survival (OS), in targeted therapy for advanced hepatocellular carcinoma (HCC). At the 2024 International Liver Cancer Association (ILCA) Conference, Professor Masatoshi Kudo from Kinki University Faculty of Medicine in Japan presented exploratory analyses on the correlation between efficacy metrics like depth of response (DpR) and duration of response (DoR) with OS benefits. He also discussed their value in guiding systemic drug therapy combined with local treatments. We interviewed Professor Kudo to share his key findings.Oncology Frontier: In your study, how are DpR and DoR defined, and what significance do they hold in evaluating treatment efficacy for patients with unresectable HCC?
Professor Kudo: When evaluating treatment responses, three key metrics stand out: ORR, DpR, and DoR. The correlation between ORR and OS is already well-established.
Depth of Response (DpR) measures the degree of tumor shrinkage and is classified into five grades:
- Grade A: Tumor shrinkage of 60%–100%
- Grade B: Shrinkage of 30%–60%
- Grade C: Shrinkage of 0%–30%
- Grade D: No change to growth of up to 20%
- Grade E: Growth exceeding 20%, indicating progressive disease (PD)
Stable disease (SD) includes cases where tumor reduction is less than 30% or growth is under 20%. This grading system enables a comprehensive assessment of the extent of tumor shrinkage.
Duration of Response (DoR) applies to responders—patients who experience tumor shrinkage greater than 30%—and measures how long the response is sustained.
Together, DpR and DoR are critical metrics, offering essential insights into the degree of tumor regression and the durability of the response. Both are indispensable for assessing treatment efficacy in patients with unresectable HCC.
Oncology Frontier: Your study indicates a correlation between DpR, DoR, and OS. Could you elaborate on the nature and strength of this association?
Professor Kudo: To date, no definitive data have established a connection between DpR or DoR and OS. In our study, we specifically analyzed these metrics in the context of first-line targeted immune combination therapies. With multiple options available for both first- and second-line treatments, we aimed to determine whether the depth and duration of response from initial therapy impact OS.
Our findings revealed a strong correlation between the five DpR grades and OS. Each grade distinctly stratified survival outcomes, demonstrating that achieving a significant depth of response with first-line therapy has a lasting effect on OS, even when patients proceed to subsequent treatments.
Additionally, among patients classified as having stable disease, those with some degree of tumor regression exhibited better survival rates compared to those without any tumor shrinkage. This underscores the importance of achieving at least partial tumor regression. For cases where significant regression cannot be attained, augmenting systemic therapy with local treatments may improve survival outcomes.
Oncology Frontier: Based on your research findings, what treatment strategies would you recommend for patients with unresectable HCC to further improve survival and quality of life?
Professor Kudo: Achieving deep responses appears to have a positive impact on survival rates. Patients with significant tumor regression tend to have better prognoses, and the proportion of patients achieving deep responses in clinical trials may indicate the potential of a treatment to improve OS.
For patients who do not achieve significant regression, strategies should incorporate locoregional therapies to alter the natural course of the disease, potentially enhancing both survival rates and quality of life.
This approach is particularly relevant for cases of stable disease with little or no tumor regression. In such scenarios, combining systemic and locoregional treatments could help improve patient outcomes. Tailoring treatment strategies based on the quality of tumor response—such as the depth and duration of response—may offer a more personalized approach, ultimately boosting both survival and quality of life for patients.
Oncology Frontier: With advances in immunotherapy and targeted therapy, how do you envision integrating DpR and DoR into future clinical trials as evaluation metrics to accelerate drug development and optimize personalized treatment for unresectable HCC patients?
Professor Kudo: Integrating DpR and DoR into clinical trials is a challenge, as these metrics reflect the best response achieved and require time for full assessment. A high rate of deep DpR in trials often indicates the potential of a therapeutic agent to improve OS. However, evaluating the depth and duration of response takes time, which could delay the outcomes of some trials.
Despite these challenges, incorporating these metrics is worthwhile because they provide valuable insights into the drug’s effectiveness in real-world clinical practice.
At the patient level, even cases achieving only stable disease (SD) could benefit from the addition of locoregional therapies to improve OS. This personalized approach, which adjusts treatments based on the depth and duration of tumor response, allows us to potentially alter the natural course of the disease in patients with unresectable HCC and improve their survival outcomes.
