Findings of the LIQUID IMPACT trial shows that non-invasive multi-analyte liquid biopsies can reveal latent actionable vulnerabilities of the cancer, which can be targeted with patient-specific combination regimens to yield clinical benefits even in heavily pretreated populations where SoC options are unavailable.
We have previously reported the findings of the RESILIENT trial1 which exposed the fallacy of the ‘single drug based on a single molecular alteration’ paradigm of several prior precision oncology trials9–14, by demonstrating that multi-analyte tumor profiling can reveal latent weaknesses of the tumor and guide efficacious and safe treatment selection in advanced refractory solid organ cancers, especially in those cases where no actionable molecular alterations were available. We also acknowledged a limitation of the study in requiring fresh tissue from a de novo biopsy tissue, since the quality and quantity of biopsied tissue could be of concern. Obtaining representative tissue is a requirement of not just ETA, but also for routine workup in oncology including histopathological evaluation (HPE) and immunohistochemistry (IHC). Factors which impact tumor tissue procurement include inaccessibility of the tumor, proximity of the tumor to vital organs or vasculature, patients’ comorbidities or even patients’ reluctance due to fear of pain or procedural complications. Where a biopsy is feasible and advised, there may be significant procedural risks, e.g., for biopsies of lung lesions are associated with risks of pneumothorax and pulmonary hemorrhage15–17. Other complications of biopsies include sepsis, air embolism, bile leak, viscus perforation and risk of tumor seeding18,19. We observed that patients who have progressed on multiple lines of treatment are often psychologically fatigued for further invasive procedures and possible hospitalization. Based on this background, we designed an Encyclopedic Liquid Biopsy (eLBx) which aimed to offer all the be benefits of a multi-analyte investigation as in case of the ETA, coupled with the safety and convenience of a simple blood draw thus avoiding all the risks of an invasive biopsy.
The primary endpoint of the trial was Objective Response Rate. While Complete Response (CR) was not observed in any patient until the date of submission, Partial Response (PR) as per RECIST 1.1 was observed in 14 out of 43 patients evaluable per protocol, yielding an Objective Response Rate (ORR) of 32.6%. Though not an endpoint of the study, Stable Disease (SD) for more than 60 days was observed in 18 other patients. yielding a Disease Control Rate (DCR) of 74.4% in the evaluable population. Median Progression Free Survival (mPFS) was 3.8 months. Among the evaluable cohort, PFS rates were 74%, 48% and 44% at 3 months, 6 months and 12 months respectively.
The outcome data from the RESILIENT trial as well as the present study demonstrate the clinical utility and efficacy of integrational multi-analyte-based approach (ETA / eLBx) in making available efficacious personalized combination regimens even in a heavily pretreated cohort of patients where further SoC options are unavailable. In routine clinical setting, where the SoC options have been exhausted, patients are often offered clinician’s choice of treatment regimens. Such treatment options may be label-agnostic and based on prior observations but lack evidence in support of efficacy and safety. On the other hand, the advantage of ETA / eLBx lies in providing the clinician with contemporaneous evidence on the tumors strengths and vulnerabilities. Thus, non-SoC treatment decisions based on such evidence have a higher probability of treatment success and clinical benefits than arbitrary ‘roll of the dice’ selection of treatment agents.
Apart from efficacy, safety of eLBx-guided treatments was an equally important consideration. Various prior meta-analyses20–22 have reviewed the safety profile of multi-drug anticancer regimens and note that it has been largely possible to administer de novo drug combinations safely in most patients and that these patients had a manageable profile of adverse events (AEs). While the profile of Adverse Events (AEs) may not be predicted in any given patient prior to therapy administration, it is possible to anticipate AEs based on available literature as well as the history of AEs in each patient. As was observed during the RESILIENT Trial as well as in the present trial, patients where the cancer had progressed following failure of multiple systemic lines of therapy tend to be physiologically fatigued due to accumulated toxicity of prior treatments. This toxicity reflected as the patient drop-out between screening and start of therapy, as well as prior to the first follow-up scan. Thus, this heavily pretreated cohort was at an inherently higher risk of AEs due to cumulative toxicities from prior treatments. However, the administration of eLBx-guided therapy regimen did not appear to increase the risk of toxicity since there were no grade IV therapy related AEs or any treatment related mortalities. Grade III AEs, where observed, were limited and manageable by administration of standard procedures.
Patients were also assessed for Quality of Life at baseline and every month based on symptomatic and functional status; alleviation of disease related symptoms and improvements in functional status implied positive findings. Based on these parameters, all patients reported stable status or improvements in either of these parameters.
Challenges for eLBx may arise where patients are weak and unable to provide blood (inability to locate vein), in which case they would also be unfit for any treatment. In the present study, several patients were excluded prior to start of therapy as well as during the first week on therapy due to accumulated toxicitues from prior treatments. However, adoption of ETA- or eLBx-guided treatments at an earlier treatment stage could obviate such limitations associated with less beneficial prior SoC regimens. One challenge in the present trial (as was also reported in the RESILIENT Trial) was the non-availability of USFDA approved treatment agents for incorporation in the TR, as several such drugs are not approved in India and possibly in several other countries.
In conclusion, the LIQUID IMPACT Trial aimed to improve on the limitations faced during the RESILIENT trial and has been largely successful in being able to provide safe, efficacious treatment options based on non-invasive evaluations of the cancer in heavily pretreated patients.