Metabolic tumor volume predicts response to loncastuximab tesirine in DLBCL

At the American Society of Hematology (ASH 2022) in New Orleans, LA, Dec 9-12, 2022, metabolic tumour volume (MTV) was reported to be a predictive biomarker for patients with relapsed or refractory diffuse large B-cell lymphoma (rel/ref DLBCL) who were being treated with loncastuximab tesirine in the LOTIS-2 trial (NCT03589469) [1]. Therefore, this biomarker, derived from PET/CT imaging, may guide individualised treatment by identifying patients who are most likely to respond well to loncastuximab tesirine. Medicom spoke with Dr. Juan Pablo Alderuccio (University of Miami, FL, USA), lead author of the study, to reflect on the outcomes of the current post-hoc analysis of the LOTIS-2 trial [1].

Loncastuximab tesirine is a humanised antibody-drug conjugate (ADC) monoclonal antibody targeting the protein CD19 used to treat adults with large B-cell lymphoma. Although MTV is an established strong prognostic factor in DLBCL, it is not yet known whether it may predict the response to loncastuximab tesirine. Since predictive biomarkers are important to guide individualised treatment and optimise outcomes, Dr Alderuccio and colleagues evaluated the association between quantitative PET/CT data and treatment response to loncastuximab tesirine in patients with rel/ref DLBCL who were enrolled in the LOTIS-2 trial (n=118). The primary objective of this study was to assess the predictive value of MTV and total lesion glycolysis (TLG) on complete metabolic response (CMR).

The results indicated that the continuous variable log2MTV was predictive of failure to reach a CMR (OR 1.52; 95% CI 1.22-1.89; P=0.002; AUC 0.744). Similarly, one unit increase in log2TLG resulted in a decreased likelihood of achieving a CMR (OR 1.49; 95% CI 1.23-1.80; P<0.001; AUC 0.758). Furthermore, increments on log₂(MTV) and log₂(TLG) were predictive of shorter event-free survival times (HR 1.28; P<0.001; HR 1.21; P<0.001) and shorter overall survival duration (HR 1.38; P<0.001; HR 1.29; P<0.001), respectively.

Medicom interviewed Dr Alderuccio to discuss the impact of these results.

What is the added value of measuring metabolic tumour volume?

Dr Alderuccio: Currently there is no predictive biomarker to assess the response to different therapies in diffuse large B-cell lymphoma. We have been using the International Prognostic Index (IPI) score based on clinical variables since the 90’s, with subsequent changes trying to improve the predicted value NCCN IPI score coming out in 2014 [2,3].

The problem we face in the clinic is that we do not base our treatment decision on the IPI score. There remains this unmet need to identify a biomarker to inform our choices. What we are attempting to show in this study is that metabolic tumour volume might fill that role, here specifically for one treatment: loncastuximab tesirine. MTV has been shown to be a robust prognosis biomarker across different lymphomas in Hodgkin lymphoma [4] and in diffuse large B-cell lymphoma [5].

The metabolic tumour volume is essentially a measurement of metabolically active tumour burden. In this specific study, we use the threshold of 41% and all the lesions that are about that threshold are included in the final tumour volume. The initial data set we used was derived from the 2 trials that led to the approval of loncastuximab tesirine in patients with 2 or more lines of therapy in diffuse large B-cell lymphoma [6,7].

What we presented at ASH 2022 was a preliminary analysis, and we are now finalising the total clinical trial cohort. But the initial data we presented were definitely interesting. What we try to assess is the predictive value of MTV. We want to predict which patients will achieve a complete response on this therapy.

Unfortunately, in the relapsed/refractory setting of DLBCL, we know that most patients who do not achieve a complete response have poor outcomes. Secondly, we assess the prognosis implications in progression-free survival and overall survival based on a screening on pre-treatment metabolic tumour volume. We also assess the tumour lesion glycolysis, and other parameter metrics, to try and compare how they perform with the metabolic tumour volume.

We delineated a specific cut-off point, that predicts outcome in this initial data set of 118 patients. What we found, albeit in this small dataset of only 118 patients, is that the metabolic tumour volume is a robust predictor of response to loncastuximab tesirine. Our hypothesis warrants further investigation.

Will MTV be developed into a useful biomarker that can be clinically actionable?

Dr. Alderuccio: Yes, assuming we are able to externally validate our findings. I think the next step for this particular study is to complete the clinical trial cohort, and see what the cut-off points are that we identify as a predictor of complete metabolic response and survival in this DLBCL population treated with to loncastuximab tesirine. We will perform internal validation with statistical bootstrapping methdology because it is not a very large clinical dataset. Once we have determined those cut-off points, the next step will be to externally validate the prognostic value of MTV in other clinical trials treating DLBCL patients with loncastuximab tesirine. Assuming that is successful, and externally validation holds up, I think we will be able to predict what patients will benefit the most to this approach, and I think the next step will be to test this biomarker prospectively in clinical trials.

Will MTV enable risk stratification to determine specifically which patients will benefit most from loncastuximab tesirine?

Dr. Alderuccio: Exactly. Because currently in lymphoma, we don’t have any biomarker that is able to predict outcomes. This is will be highly important for the lymphoma community.

Is there a correlation between genomics and metabolic tumour volume?

Dr. Alderuccio: That is a very interesting question. We haven’t yet explored the correlation between genomics and higher metabolic tumour volume. We are, however, planning that very analysis as a priority going forward.

But if I were to speculate, I think we can expect that patients with higher metabolic tumour volumes will be characterised by more complex genomic features associated with poor prognosis, such as TP53 mutation and others. The challenge with diffuse large B-cell lymphoma is that there are no specific mutations that are commonly associated with worse prognosis like in other types of diseases; it is a very heterogeneous disease. Nevertheless, I definitely think that there can be a correlation there between genomics and MTV. An additional step forward will be to correlate MTW with radiomics, and eventually even with radiogenomics. The challenge there will be to find specific features extracted from the imaging data that may indicate the presence of specific genetic mutations.

I think it is very exciting times for lymphoma research. I think the data extracted from imaging data can be extremely useful in treatment prediction for outcomes and survival. Moreover, the incorporation of machine learning is allowing us to process very large data sets, and then go back to our clinic and match what we find in the patient with what we find in their tumour profiles, either genomically, metabolically, or radiographically.

Take-home messages?

Dr. Alderuccio: I think this is very exciting work, in an exciting field, which is rapidly changing. We need further validation, especially external validation, as any biomarker does, in order to prove the efficacy to discriminate between respondents and non-respondents and prognosis. Then, I think the next step will be to prove this biomarker prospectively. Hopefully we will be able to incorporate metabolic tumour volume into our clinical practice in the near future.

References

1. Alderuccio JP, et al. Metabolic Tumor Volume Predicts Outcomes in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Trial. Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Poster II, ASH 2022, 10-12 December, LA, USA
2. Shipp et al. A predictive model for aggressive non-Hodgkin’s lymphoma. New England Journal of Medicine 1993 September 30, 329 (14): 987-94
3. Zhou et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014 February 6, 123 (6): 837-42
4. Cottereau AS, et al. Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood. 2018 Mar 29;131(13):1456-1463.
5. Kostakoglu L, et al. Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study. Haematologica. 2022 Jul 1;107(7):1633-1642.
6. Hamadani M, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021 May 13;137(19):2634-2645.
7. Caimi PF, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800.

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Posted on 28 December, 2022