Response to Immune Checkpoint Antibodies: Not All Responses Are Created Equal Free

In this issue of Clinical Cancer Research, Gauci and colleagues (1) describe long-term survival among those patients who respond to PD-1 or PD-L1 immune checkpoint inhibitors for the treatment of various malignancies. The data was pulled from a phase I study of anti–PD-1/PD-L1 monotherapy and retrospectively analyzed during a period of 5 years. A total of 262 patients received at least one dose of pembrolizumab, nivolumab, atezolizumab, or durvalumab. The maximum duration of treatment varied between protocols (12 months for patients treated with durvalumab or atezolizumab, 24 months with pembrolizumab and treatment to progression with nivolumab). Patients were retreated if they progressed after discontinuation of therapy. Responders were further categorized as long-term and short-term. At the time of the data collection, 20% [95% (confidence interval) CI: 15–25] of the overall population was still alive 2 years after initiation of immunotherapy. A long-term response was defined as a response lasting ≥2 years.

The overall objective response rate of 29% was consistent with previously published data. Analysis focused on the partial and complete responders. In those patients, the 3-year and 5-year overall survival (OS) percentages were 84% and 64%, respectively. Patients with a complete response (CR) had, by far, the more favorable outcomes, with no deaths or recurrences during the follow-up time period. Patients with a partial response (PR) frequently experienced disease progression and succumbed to their disease, suggesting that not all responses are created equal.

The majority of current research is focused on nonresponders and exploring mechanisms of resistance in that patient population. To date, no studies have stratified responder subsets, separately analyzing outcomes in partial and complete responders. A notable data gap remains for patients who have stable disease as their best response; not addressed in this analysis or others. Gauci and colleagues strongly supports the conclusion that depth of response matters. This is hardly surprising in light of long-standing data confirming clearance of clinical and molecular evidence of disease equates with long-term outcomes in patients with chronic myeloid leukemia treated with ABL kinase inhibitors and other hematologic malignancy populations treated with chemotherapy. Data from this study supports exploration of abbreviated courses of therapy in patients with documented or predicted CRs.

There has been an explosion in the number and type of predictive and/or on-treatment biomarkers being explored in the realm of immunotherapy. High mutational burden has been well-documented to correlate with likelihood of response, but the ability to specifically diagnose mutated neoantigens that will drive response remains elusive. Baseline markers of T-cell activation and exhaustion and even tumor cell cooption of PD-L1 have only marginally aided in response prediction. On the basis of current evidence, early on-treatment analysis of tumor biopsies and/or blood are the most effective methods of monitoring effective tumor/immune engagement. However, this evidence has been generated from serial tumor biopsies, which is hardly feasible in the routine care of patients with advanced cancer. Blood-based monitoring strategies are now gaining traction and, in some cases, have been associated with direct evidence of immune activation in tumors.

Although tumor tissue and blood-based biomarker research is gaining predictive value, imaging modalities may overcome limitations of both, in predicting responders and guiding discontinuation or escalation of therapy (in the form of combination regimens; Fig. 1). Use of PET-CT with ¹⁸F-fluorodexoxyglucose (¹⁸F-FDG) remains a viable option for detecting activity of disease. In patients with melanoma, Gibney and colleagues (2) presented data on patient outcomes following discontinuation of therapy after assessing CT, PET-CT, or biopsy of residual disease. Twenty-one of 96 patients discontinued treatment at the discretion of the provider or personal preference. These patients were further stratified into response by CT, PET, or positive PET-CT and negative biopsy. The results suggest that PET/CT may be one strategy for discontinuation of therapy.

Although viable cancer cells typically show FDG avidity, a metabolically active immune cell infiltrate can be difficult to distinguish from tumor. Preclinically, imaging techniques designed to monitor CD8⁺ and CD3⁺ T-cell infiltration and/or PD-1/PD-L1 expression have been explored. Results of those studies reveal limitations in recognizing T-cell exhaustion or anergy, leading to immunotolerance. Granzyme B PET imaging may better predict an immunotherapy response by differentiating active infiltrative T cells from the total tumor immune infiltrate. During the immune response, CD8⁺ T cells and natural killer cells release a serine-protease, granzyme B. In 2017, Larimer and colleagues (3) published preclinical proof-of-concept for the use of granzyme B PET imaging. This imaging modality was able to distinguish responding mice from progressors. In subsequent work, this method was shown to be capable of detecting responses to other immune checkpoint antibodies or combinations (4). This method is being readied for clinical investigation.

The current portfolio of immunotherapy trials exceeds the available pool of clinical trial participants. One of the more common designs for trials investigating novel agents on a PD-1/PD-L1 backbone is to add a second agent at the time of disease progression. In aggressive cancers such as melanoma, non–small cell lung cancer, and squamous cell carcinoma of the head and neck, many patients clinically deteriorate and become ineligible for such studies. Furthermore, it is not clear that PD-1/PD-L1 antibody–induced T-cell activation persists in patients who have received months of therapy and who have clinically evident de novo resistance. Detecting response and resistance to available PD-1/PD-L1 antibody–based regimens would accelerate proof-of-concept studies, allowing for prioritization of agents to study further. In PD-1/PD-L1–indicated cancers, unnecessarily long treatment duration definitely increases cost and may lead to an increase in immune-related adverse effects.

J.V. Cohen is a consultant for Sanofi-Genzyme. K.T. Flaherty reports receiving commercial research grants from Novartis and Sanofi, and is a consultant/advisory board member for Novartis, Bristol-Myers Squibb, Merck, Amgen, Genentech, and Sanofi; he would also like to report the following relationships: serves on the board of directors of Loxo Oncology, Clovis Oncology, Strata Oncology, and Vivid Biosciences, serves on the corporate advisory board of X4 Pharmaceuticals and PIC Therapeutics, is a scientific advisory board member for Asana, Adaptimmune, Fount, Aeglea, Array BioPharma, Shattuck Labs, Arch Oncology, Tolero, Apricity, Oncoceutics, Fog Pharma, and Tvardi, and is a consultant to Takeda, Verastem, Checkmate, and Boston Biomedical. No other potential conflicts of interest were disclosed.

Conception and design: J.V. Cohen, K.T. Flaherty

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.V. Cohen, K.T. Flaherty

Writing, review, and/or revision of the manuscript: J.V. Cohen, K.T. Flaherty