Durvalumab Plus Olaparib or Cediranib Leads to Disease Stabilization in Leiomyosarcoma

The combination of durvalumab (Imfinzi) plus either olaparib (Lynparza) or cediranib resulted in disease stabilization of 33% in patients with leiomyosarcoma (LMS), which supports further immunophenotype characterization in this disease, according to Albiruni Ryan Abdul Razak, MD.

Initial data from the phase 2 DAPPER study (NCT03851614), which were presented during the 2021 ASCO Annual Meeting, indicated that although no complete or partial responses were achieved with the combination regimens, 33.3% of the 24 evaluable patients in the LMS cohort achieved stable disease. Moreover, durable disease control was achieved in 20.8% of patients (n = 5); 4 of these 5 patients received durvalumab plus olaparib.

Moreover, the median progression-free survival with durvalumab/olaparib was 9 months (95% CI, 3.17-8.00) vs 4 months (95% CI, 2.2-6.1) with durvalumab/cediranib. At a median follow-up of 9.8 months (range, 0.8-24.4), 73.3% of patients (n = 22) were still alive.

Additional results from a tumor kinetic analysis indicated that among 20 evaluable patients, more than 60% (n = 13) experienced a reduction in tumor growth rate (TGR) on both arms. The reduction in TGR on treatment vs baseline was found to be significant with durvalumab/olaparib (0.2 vs 5.1; 95% CI, 0.2-4.3; P = .031), but not with durvalumab/cediranib (1.3 vs 2.9; 95% CI, 0.2-2.7; P = .068).1

“The concept of turning ‘cold’ tumors into ‘hot’ [ones] still needs further interrogation. We need to understand, at a molecular level, what really happens to these tumors [with this treatment,] and I hope further data [will shed further light on this],” Razak said. “Certainly, there is a subset of patients who benefit from combination treatment of a PD-L1 inhibitor with either cediranib or olaparib, but the key [question to focus on moving forward] is, how do we [know] who [will] benefit [from this kind of approach] vs who will not?”

In an interview with OncLive^®, Razak, an associate professor at the University of Toronto, medical oncologist at Princess Margaret Cancer Centre & Mount Sinai Hospital, discusses the rationale for examining durvalumab with either olaparib or cediranib in patients with LMS, key data reported with this approach, and next steps for the phase 2 DAPPER study.

OncLive^®: What was the rationale for the phase 2 study?

Razak: The DAPPER study consisted of 3 different cohorts. We presented the third cohort, which is the LMS cohort, [at the 2021 ASCO Annual Meeting]. The rationale of the study is the same across the 3 different groups analyzed, which included LMS, pancreatic cancer, and microsatellite stable colon cancer. These are considered to be immune ‘cold’ tumors, or tumors that do not respond readily to immunotherapy. In this particular trial, our [goal] is to turn the tumor phenotype from ‘cold’ to ‘hot.’ The hope is that with this strategy, [we can increase] the response to immunotherapy within these 3 tumor subtypes.

Could you expand on the design of the trial? What were the methods that were utilized to conduct this research?

This multiomic study is not meant to answer purely an efficacy-type question, but rather to [provide] an insight on what really happens to these tumors when such strategies, meaning combination therapies, are given. The 2 combination [regimens] that we [investigated] were the PD-L1 inhibitor durvalumab with the PARP inhibitor olaparib, which was arm A of the study, or [durvalumab with] the antiangiogenic inhibitor cediranib, which was arm B.

The study was designed in such a way that there is a good distribution of the 3 different tumor subtypes, as well as between the 2 arms of the treatments, but they are not meant to be compared clinically; they are meant to [provide insight into] what happens in the different arms.

Within this study, we have a lot of multiomics interrogation. For example, we have PET biopsy as an optional biopsy at [the time of] progression, and we're going to subject that to gene expression and genomics interrogation. There is stool collection for microbiome assessments, as well as radiomics assessments. We are looking at digital readouts of these scans to try and come up with a biomarker based on artificial intelligence platforms to decipher these signals. We also have a serial blood test that has been taken and the hope is that we can interrogate circulating tumor DNA estimations within this patient population.

What were the key findings from this research?

Within the LMS cohort, which are the only data that have been presented thus far, we haven't seen much in terms of responses. However, we saw a number of patients, especially in the olaparib arm, who have prolonged disease stabilization. In fact, 1 of the patients was treated for the full 12 months and is still stable many months after. The tumor kinetics, or the rate at which the tumor grew, also changed. There is a deceleration of tumor growth—especially in the olaparib arm. We also found that the regimen is tolerable. We did not [observe] high-grade toxicities that led to treatment discontinuation. [We need to wait for] the data to mature.

Could you expand on the multiomics assessments and subanalyses that are being conducted?

Where the study will harness its full potential is in the upcoming multiomics assessments, [which are] happening as we speak. At the moment, we are contouring all the scans for radiomics assessments. We are performing the genomic sequencing for tumor, as well as stool, for the microbiome studies. We’re also working [with the] circulating tumor DNA.

Additionally, we have looked at multiplex immunohistochemistry, examining the immune phenotype of the tumors before and after [treatment]. It should be noted [that this was done on] a limited sample, not the whole study, because we haven't finished the study at the time of strength submission. [We have seen] some interesting findings. For example, in the patients who had the best disease stabilization, [specifically] 12 months and beyond, we have seen that the tumor immunophenotypes have changed; there is increase in tumor-infiltrating lymphocytes and so forth.

What are some open questions to address with ongoing or future efforts?

For patients who have benefited from the regimen, we don’t know whether this is truly from the effects of the combination or the effects of the PARP inhibitor. Matthew Ingham, MD, of Columbia University Herbert Irving Comprehensive Cancer Center, presented in an oral session data with temozolomide and olaparib, and for a heavily pretreated population, a response rate of 27% is considered very respectable, albeit the number of patients was small. Still, this is a good signal to tell us that something [is working] there.

This goes down to the concept of BRCAness in leiomyosarcoma. A few groups, including us in Toronto, have published data to show that there is a degree of BRCAness in leiomyosarcoma—especially in uterine leiomyosarcoma. However, it is not clear how we can exploit that information to increase the therapeutic benefit in patients at the end of the day. We are still working that out as research [efforts continue].

Were any other efforts presented at ASCO that were particularly intriguing?

Dr. Ingham's [presentation is] one that is closely related to the work that we presented at the meeting, but several other [efforts] were also interesting. For example, Brian Van Tine, MD, PhD, of Siteman Cancer Center, [presented] data on using a metabolomics approach [with pegylated arginine deiminase] together with gemcitabine and docetaxel, that were also unprecedented; this [approach] warrants a further look. It's nice to see the data, because we know that he's been working on this for a number of years and to see it to fruition with great results is highly interesting.

A number of other [efforts were intriguing]. Dr Van Tine also presented data on AL3818 [catequentinib, anlotinib], which will probably set a new standard in addition to what is available in synovial sarcoma.

Reference

1. Ayodele O, Wang BX, Pfister TD, et al. A phase II, open-label, randomized trial of durvalumab (D) with olaparib (O) or cediranib (C) in patients (pts) with leiomyosarcoma (LMS). J Clin Oncol. 2021;39(suppl 15):11522. doi:10.1200/JCO.2021.39.15_suppl.11522