Multicancer early detection (MCED) tests demonstrated a strong capacity for delivering accurate and specific cancer signal origin (CSO) predictions across various tumor types. These results suggest that MCED tests should be included as a complement to existing single-cancer screening tests.

Specifically, data from The Circulating Cell-Free Genome Atlas Study (CCGA; NCT02889978), published in 

 showed that cancer signals were detected across more than 50 tumor types and that the MCED tests demonstrated a specificity for cancer signal detection of 99.5% (95% CI, 99.0%-99.8%). The overall sensitivity for cancer signal detection was 51.5% (n = 1453/2823; 95% CI, 49.6%-53.3%) and the sensitivity of the tests increased with disease stage; sensitivity for stage I disease was 16.8% (95% CI, 14.5%-19.5%), 40.4% (95% CI, 36.8%-44.1%) for stage II, 77.0% (95% CI, 73.4%-80.3%) for stage III, and 90.1% (95% CI, 87.5%-92.2%) for stage IV.

Overall, the accuracy of CSO prediction in true positives was 88.7% (95% CI, 87.0%-90.2%).

Investigators also reported that the MCED test demonstrated a cancer signal detection sensitivity of 40.7% (95% CI, 38.7%-42.9%) in an analysis was conducted in a cohort of patients with 12 prespecified cancers which account for approximately 66% of annual cancer deaths annually in the United States. Specifically, this cohort included patients with either anal, esophageal, lung, pancreatic, bladder, head and neck, stomach, ovarian, liver/bile duct, and colorectal cancers, as well as lymphoma and plasma cell neoplasms.

Further, an analysis of patients with stage I-III disease showed that the sensitivity of cancer signal detection with the MCED tests was 67.6% (95% CI, 64.4%-70.6%).

“Finding cancer early, when treatment is more likely to be successful, is one of the most significant opportunities we have to reduce the burden of cancer,” Eric Klein, MD, the chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic, said in a press release from ESMO.

 “These data suggest that, if used alongside existing screening tests, the multicancer detection test could have a profound impact on how cancer is detected and, ultimately, on public health.”

Widespread detection of cancer prior to stage IV disease could reduce cancer-related deaths by more than 15% within 5 years. Five single-cancer screening tests available for use in the United States for detection of breast, colorectal, cervical, lung, and prostate cancers, which account for 42% of annual cancer incidence rates. The use of cancer screening tests have contributed to the reduction of cancer-specific mortality, however, they are associated with high rates of false positives, over-diagnosis, and over treatment.

MCED tests represent a potential new approach to detecting signals for multiple cancer types by utilizing cell-free DNA (cfDNA) or other circulating analytes in the blood shed by tumors. As such, CCGA study investigators sought to develop and utilize a MCED test to detect cancer signals across multiple cancer types, as well as predict CSO with just a single blood draw.

From August 2016 and February 2019, this prospective, multi-center, case-control, observational study with longitudinal follow-up, enrolled 15,254 patients from 142 sites in North America. The study was then divided into 3 prespecified sub-studies that included a discovery cohort, a cohort that examined training and validation with the selected and updated assay and classifiers, and clinical validation cohort, reported here.

Patients eligible to enroll on the study were those 20 years and older, who received a diagnosis of cancer and/or were scheduled to undergo biopsy or surgical resection for a confirmed or highly suspected malignancy. Those who had previously undergone chemotherapy, radiotherapy, or definitive local therapy were not eligible to enroll.

The primary end point of the sub-study was to evaluate MCED test performance for cancer signal detection, CSO prediction, and the rates of both combined. Key secondary end points included test performance by age group, test performance for cancer signal detection by method of cancer diagnosis, and test performance for cancer signal detection in a prespecified group of 12 cancer classes.

In total, 5309 patients were enrolled on the third sub-study, 4077 of whom were included in the analysis. Of the evaluable patients, 2823 had a confirmed cancer diagnosis, and 1254 did not have a cancer diagnosis. The most common reasons for exclusion from the analysis were incomplete 1-year follow-up for noncancer participants (n = 324), presence of nonmalignant conditions at enrollment (n = 283), and unconfirmed cancer or treatment status at blood draw (n = 171).

Patients had a mean age of 60.6 years, and a majority were female (55.4%) and White (81.2%). Among patients with a confirmed cancer diagnosis, most presented with stage I or stage II disease (54.9%).

“These data add to a growing body of literature that supports the use of next-generation sequencing for the detection of cell-free DNA in blood samples as a tool for earlier detection of common cancers that account for a significant number of deaths and other health problems worldwide,” Klein said. “In addition, a screening test that requires only a simple blood draw could provide an option for communities that have poor access to medical facilities.”

Klein E, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. 

. Published online ahead of print June 23, 2021. doi:10.1016/j.annonc.2021.05.806

Blood test for early detection of cancer: final study results support screening use. News release. European Society for Medical Oncology. June 25, 2021. Accessed June 25, 2021. 

This article was originally published on OncLive as 

“Blood-based Test Shows Promising Accuracy in Detecting Cancer-Signal Across Multiple Tumor Types”

Articles

Multicancer early detection tests provided specified and accurate cancer signal origin detection across more than 50 tumor types. 

Blood-Based Tests Should Be Included in Single-Cancer Screenings

Journal of the National Comprehensive Cancer Network

 demonstrated that brain imaging should become routine for patients with advanced or metastatic renal cell carcinoma (mRCC) with high metastatic burden and who have progressed following first-line therapy treatment.

Results from a large multi-institutional cohort study found that 4.3% (95% CI, 3.3%-5.3%; n = 72) of 1689 patients with mRCC had incidental brain metastases without documented neurological symptoms. The median overall survival (OS) in these patients was 10.3 months (range, 7.0-17.9) and the 1-year OS rate was 48% (95% CI, 37%-62%).

When stratified by International Metastatic RCC Database Consortium (IMDC) risk status, survival outcomes were not found to significantly differ between those with favorable-, intermediate-, or poor-risk patients vs the use of log-rank testing (

= .3). The median OS in the favorable-risk, intermediate-risk, and poor-risk subgroups was 12.7 months (range, 4.8–not evaluable [NE]), 12.4 months (range, 7.4-19.7), and 4.5 months (range, 3.8–NE), respectively. The 1-year OS probability of favorable-, intermediate-, and poor-risk disease was 53% (95% CI, 33%-86%), 52% (95% CI, 38%-71%), and 29% (95% CI, 9%-92%), respectively.

“With 4% overall incidence in this cohort, one might conclude that baseline brain imaging should be considered in all patients with metastatic kidney cancer, particularly those with multiorgan involvement and/or pulmonary metastases” lead study author Ritesh R. Kotecha, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, stated in a press release.

Although brain metastases occur in approximately 5% to 20% of patients with mRCC, no standard guidelines exist for brain imaging in the absence of symptoms. As such, asymptomatic patients may not be included in historical rates, making this population difficult to define. Earlier detection of brain metastases through standardized screening guidelines could help to solidify the rates among patients with mRCC, as well as improve survival outcomes.

To characterize those with mRCC who were diagnosed with asymptomatic brain metastases, investigators performed a retrospective review of data from patients who were screened prior to entering clinical trials. Data from 68 clinical trials performed at Memorial Sloan Kettering Cancer Center and Gustave Roussy between 2001 and 2019 were reviewed and utilized to evaluate baseline characteristics, as well as reported symptoms. Any clinical trials that did not require brain imaging for participation were not reviewed.

“Brain imaging is routinely obtained for [patients with] kidney cancer with symptoms that suggest central nervous system [CNS] metastases, but none of the patients with brain metastases included here were symptomatic,” senior researcher Martin H. Voss, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, stated in the release. “In current practice, the chest, abdomen, and pelvis are routinely imaged from the time that metastatic disease is first detected, yet many oncologists do not image the brain.”

Of the 72 patients found to have incidental brain metastases without neurologic symptoms, the median age at the time of cancer diagnosis was 56 years (range, 37-77) and 75% of patients were male. Additionally, 88% (n = 63) of patients had undergone prior nephrectomy, and 68% had received at least 1 prior line of treatment. All patients had a clear cell histologic subtype, and 60% (n = 43) presented with stage IV disease at initial diagnosis. In terms of brain metastases characteristics, 63% (n = 45) of patients had a solitary lesion, and CNS involvement was multifocal in 38.5% of patients.

Among the 72 patients reviewed, 61 had additional follow-up data that indicated they received brain metastases site-directed therapy. Of those patients, 83% (n = 52) received a corticosteroid, and 93% (n = 57) underwent site-specific therapy, such as stereotactic radiotherapy (72%), whole-brain radiotherapy (14%), surgical resection (11%), or both radiotherapy and resection (4%). Moreover, the median time between brain imaging and site-directed therapy was 30 days (range, 4-262).

Additional data indicated that OS was not found to differ significantly in patients with solitary disease vs those with multifocal disease. The median OS for patients with solitary disease was 14.2 months (range, 9.5-21.6) vs 5.8 months (range, 4.1-18 months) for those with multifocal disease; the 1-year OS probability rates were 57% (95% CI, 44%-74%) and 33% (95% CI, 19%-58%), respectively. Difference across other subgroups, including lesion size, also did not show statistical differences.

“The findings in this study are important for 2 reasons. First, they show that the overall prognosis of patients with brain metastases is consistently worse than the broader population of patients with metastatic renal cell carcinoma. We need to develop a deeper scientific understanding of why this patient population has a worse outcome, and we need to include them in future clinical trials,” Eric Jonasch, MD, a professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in the release. “Second, they underscore the utility for MRI imaging of all patients with metastatic renal cell carcinoma both at initial diagnosis, and at regular intervals, to detect occult brain metastases, since specific treatment strategies are required for this patient population.”

Kotecha RR, Flippot R, Nortman T, et al. Prognosis of incidental brain metastases in patients with advanced renal cell carcinoma. 

2021;19(4):432-438. doi:10.6004/jnccn.2020.7634

JNCCN study: important potential role for routine brain imaging in advanced kidney cancer. News release. The National Comprehensive Cancer Network. April 13, 2021. Accessed April 22, 2021. 

This article was originally published on OncLive as “

Brain Metastases Occur in Significant Percentage of Advanced RCC, Underscoring Potential Role for Routine Brain Imaging”

New data emphasizes need for routine brain imaging in patients with advanced or metastatic renal cell carcinoma with prior treatment and high metastatic burden. 

Brain Imaging Guidelines Needed for Patients with Metastatic Kidney Cancer

The nomogram, a new prognostic tool, has exhibited a capability to predict outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with lutetium-177 (177Lu) prostate-specific-membrane antigen (PSMA). Researchers hope this new tool could be useful in informing future trial designs and clinical decisions, according to data from a retrospective study published in 

The nomograms, which were developed by investigators at the UCLA Jonsson Comprehensive Cancer Center and those from 5 other institutions, included predictive variables, such as the time since initial diagnosis of prostate cancer, chemotherapy status, hemoglobin concentration at baseline, and [68Ga]Ga-PSMA-11 PET/CT parameters such as molecular imaging TNM classification and tumor burden.

Results from the study showed that the C-index of the overall survival (OS) model was 0.71 (95% CI, 0.69-0.73). Similar C-indices were observed with internal validation (0.71; 95% CI, 0.69-0.73) and external validation (0.72; 95% CI, 0.68-0.76). Moreover, the C-index for the prostate-specific antigen (PSA) progression-free survival (PFS) model was 0.70 (95% CI, 0.68-0.72). Again, similar C-indices were achieved with both internal (0.70; 95% CI, 0.68-0.72) and external (0.71; 95% CI, 0.68-0.74) validation. As such, both models were found to have acceptable calibration with predictions that correlated with observed outcomes.

“Until now, there has been no validated tool to adequately predict the response of patients with advanced metastatic prostate cancer to Lu-PSMA treatment,” said lead author Andrei Gafita, MD, a postdoctoral scholar in the Ahmanson Translational Theranostics Division of the department of molecular and medical pharmacology at the David Geffen School of Medicine, said in a press release.2 “Most important, this study suggests that screening with PSMA PET imaging could help to select patients who are most likely to benefit from this treatment.”

177Lu-PSMA is a radiolabeled small molecule inhibitor that binds with high affinity to PSMA and delivers β particle radiation. In June 2021, the FDA granted a breakthrough therapy designation to the agent based on results from the phase 3 VISION trial (NCT03511664), which demonstrated that when combined with standard-of-care treatment, 177Lu-PSMA resulted in a 40% reduction in the risk of death vs SOC alone in patients with progressive PSMA-positive mCRPC.

Although many efforts have been made to understand tumor heterogeneity and to develop prognostic nomograms in patients with mCRPC who receive frontline or second-line treatment, no models exist to efficiently evaluate the prognosis for patients who are later in their disease course and are potentially eligible for treatment with 177Lu-PSMA. As such, investigators sought to develop nomograms as a way to predict outcomes with the therapy in this population.

For the multicenter, retrospective study, predictive nomograms were developed using data collected from 6 institutions across the United States, Germany, and Australia—all of whom had screened patient who had received treatment with 177Lu-PSMA from December 10, 2014, to July 19, 2019, as part of a phase 2 clinical trial (NCT03042312, ACTRN12615000912583).

To be eligible, patients had to have received an intravenous injection of 177Lu-PSMA, at a dose ranging from 6.0 GBq to 8.5 GBq once every 6 to 8 weeks for a maximum of 4 to 6 cycles, without experiencing disease progression or notable toxicity. Additionally, patients had to have a [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and information on survival outcomes available. Patients who received 18F-labeled PSMA-PET at baseline were excluded.

Overall, 270 were enrolled to the trial; these patients were assigned to a development cohort for model development (n = 196) or a validation cohort for model validation (n = 74). The primary outcomes for the nomograms were OS and PSA-PFS.

Data on 26 different pretherapeutic parameters were collected from patients, 18 of which were tested in models as putative predictors of outcome after treatment with 177Lu-PSMA. Some of the pretherapeutic parameters included information on demographics, initial diagnosis of prostate cancer, treatment history, baseline clinical status, baseline laboratory tests, and baseline [68Ga]Ga- PSMA-11 PET/CT tumor characteristics.

Among the 270 patients included, the median age across the cohorts was 71 years (range, 65-76), and the median time since initial diagnosis was 6.5 years (range, 4-12). Fifty-eight percent of patients had received treatment with 177Lu-PSMA as part of compassionate access programs, and 42% had received the therapy as part of a clinical trial. The therapy was administered for a median of 3 cycles per patient. Patients had received a median of 3 prior systemic treatments, with 95% having received treatment with second-generation antiandrogens and 81% having previously received chemotherapy.

At a median follow-up of 21.5 months, 83% of the 270 patients had died and 91% experienced PSA progression.

Additional data from the study indicated that the estimated 12-month OS rate was 54% (95% CI, 48%-60%), and the estimated 18-month OS rate was 34% (95% CI, 29%-40%). Predictors selected in this model included time since cancer diagnosis, chemotherapy status, baseline hemoglobin concentration, bone and liver involvement status, number of metastatic lesions, and tumor SUVmean.

Moreover, the estimated 3-month PSA-PFS rate was 64% (95% CI, 58%-70%); at 6 months, the estimated rate was 38% (95% CI, 32%-43%). Selected predictors for this model were time since cancer diagnosis, chemotherapy status, pelvic nodal status, bone and liver involvement status, and tumor SUVmean.

Additionally, patients in the development cohort, the validation cohort, and the complete set were stratified into 2 risk groups using the calculated optimal cutoff for the risk scores; this was 197 points for the OS nomogram and 178 points for the PSA-PFS nomogram.

In the development cohort, the median OS for low- vs high-risk patients were 19.1 months (95% CI, 17.1-21.1) and 8.4 months (95% CI, 7.4-9.4), respectively (

<.0001). The median PSA-PFS in this cohort was 9.4 months (95% CI, 6.6-12.1) in patients who were high risk vs 3.3 months (95% CI, 2.9-3.7) in low-risk patients (

In the validation cohort, patients who were low risk were found to have a significantly longer median OS than those who were high risk, at 24.9 months (95% CI, 16.8-27.3) vs 7.4 months (95% CI, 4.0-10.8), respectively (

<.0001); this was also true with regard to PSA-PFS, at 6.6 months (95% CI, 6.0-7.1) vs 2.5 months (95% CI, 1.2-3.8), respectively (

In complete set, the median OS for low- and high-risk patients were 19.9 months (95% CI, 17.5-22.3) vs 8.2 months (95% CI, 7.2-9.1), respectively (

<.0001). The median PSA-PFS in these subsets were 8.8 months (95% CI, 7.3-10.3) vs 3.3 months (95% CI, 2.8-3.7), respectively (

“The findings from the research are encouraging and may provide the foundation for patient selection for LuPSMA therapy,” Gafita said. “Nevertheless, until its clinical validity is demonstrated in prospective trials, the tool should be used cautiously and should not replace the clinical judgement of treating physicians.”

Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. 

. Published online July 8, 2021. doi:10.1016/S1470-2045(21)00274-6

Tool helps predict who will respond best to targeted prostate cancer therapy. News release. UCLA. July 8, 2021. Accessed July 21, 2021. 

Novartis receives FDA breakthrough designation for investigational 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Novartis. June 16, 2021. Accessed July 21, 2021. 

Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 

. 2021;39(suppl 15):LBA4. doi:10.1200/JCO.2021.39.15

This article was originally published on OncLive as “New Tool Could Help Predict Outcomes with 177Lu-PSMA in Metastatic Castration-Resistant Prostate Cancer”

Nomogram May Have the Power to Predict Treatment Outcomes in Patients with Prostate Cancer Subtype 

Telaglenastat (CB-839) did not produce a significant improvement in progression-free survival (PFS) when administered in conjunction with cabozantinib (Cabometyx) to treat metastatic renal cell carcinoma (mRCC). Despite these results, Nizar Tannir, MD, FACP, says telaglenastat may still produce positive results when combined with other therapeutic partners in a biomarker-selected populations with a high dependence on glutamine/glutaminase.

Results from the phase 2 CANTATA trial (NCT03428217), which were presented during the 

, showed that the combination yielded a median of 9.2 months (95% CI, 7.6-11.1) vs 9.3 months (95% CI, 7.6-11.0) with cabozantinib alone (hazard ratio [HR], 0.94; 95% CI, 0.74-1.21; 

 = .653) in this patient population (n = 444). Moreover, the overall response rate (ORR) was 31.2% with the combination vs 27.8% with cabozantinib alone, which was also not determined to be statistically significant.

“One should not be discouraged by a negative trial. So many agents have very strong [preclinical] rationale, they show encouraging results in phase 1 [trials], and then in large, randomized phase 3 trials, they end up being negative,” Tannir said. “It shows that we still have a long way to go [in terms of selecting] the proper patient population [for this regimen, and maybe, bringing back the concept of a biomarker-driven trial.”

®, Tannir, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, and Ransom Horne, Jr. Professorship for Cancer Research, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the results of the phase 2 CANTATA trial with telaglenastat plus cabozantinib and future research directions for the glutaminase inhibitor.

®: Could you speak to the rationale for evaluating telaglenastat in the CANTATA trial?

: [Many research efforts] have focused on targeted therapy. For example, in kidney cancer, [we know that] angiogenesis is important. [We also know the] importance of immune checkpoint inhibitors in many tumor types. [However,] tumor metabolism has emerged as an important area of research.

If we look at normal cells, [they] produce energy through glucose conversion, through the glycolysis mechanism, and by producing adenosine triphosphate [ATP] in the tricarboxylic acid cycle [TCA] cycle. Tumor cells, on the other hand, must rely on [a pathway] other than the glucose pathway for their metabolism, because there is conversion of glucose to lactate through the Warburg effect; that is where glutamine comes [in].

Telaglenastat is a glutaminase inhibitor that blocks the conversion of glutamine to glutaminase. Many tumor types rely on glutamine and glutaminase to produce their energy. This is the rationale for producing this agent.

Additionally, phase 1 trial [NCT02071862] combined 

 in a small number of heavily pretreated patients. We observed an ORR of 50% and a disease control rate of 100% with the regimen. This provided a good foundation to conduct this large, phase 3 trial.

What was the design of the study, and the key objectives of the research?

[CANTATA] is a large global, randomized, placebo-controlled, double-blind phase 3 trial. [Investigators] looked at combining an agent that is FDA approved in the salvage setting, the VEGF TKI cabozantinib, [with telaglenastat]. It is a rational combination based on data from preclinical studies, [which] showed the combination of everolimus [Afinitor] plus telaglenastat, [as well as] the combination of cabozantinib plus telaglenastat, had synergy in both in vitro [and] in vivo models. That is the scientific rationale for this combination.

The design [of the trial] was simple; [we evaluated] telaglenastat plus cabozantinib vs placebo plus cabozantinib in the second- and third-line treatment setting. Patients had to have received [prior treatment with] either nivolumab [Opdivo] plus ipilimumab [Yervoy] or antiangiogenic inhibitors, and up to 2 prior lines of therapy. Participants were randomized [in a] 1:1 [fashion]. The primary end point of the study was PFS. The trial was powered to answer the question of whether the combination of telaglenastat plus cabozantinib could produce an improvement in PFS, as assessed by an independent radiology committee [IRC]. A [total] of 444 patients were accrued to the trial.

[Additionally,] there were some assumptions [to note], which first started with the control arm. We know that in the phase 3 METEOR trial [NCT01865747], which compared single-agent cabozantinib with everolimus in the second- and third-line setting and beyond, [results showed a] median PFS of 7.4 months. As such, there were assumptions made for this trial to design it and calculate the sample size. We used 8 months as the median PFS for the control arm, and the HR was set at 0.69; that is how we came up with 444 [as our target number of patients to accrue to the trial].

What were the results that read out during the 2021 ASCO Annual Meeting?

Unfortunately, results did not show an improvement in PFS with the combination of telaglenastat plus cabozantinib compared with placebo plus cabozantinib. The median PFS by IRC assessment in both arms proved to be very similar, at 9.2 months and 9.3. months, [respectively]; this shows that there is really no advantage or [PFS] benefit [derived from] the [experimental] combination. The data regarding responses to treatment were consistent [with this finding]; the ORR was 31% in the experimental arm vs 28% in the placebo arm, so no real difference between the arms.

[In terms of] overall survival [OS], most patients were still alive at the time of the analysis, or at the time of data cutoff, which was August 31, 2020. [Approximately] 35% of the patients had died on the experimental arm vs [approximately] 31% on the placebo arm. [The OS data are still] considered to be immature. In the future, we will have longer follow-up data from the study to assess OS. However, in terms of the primary end point of PFS, no difference [was observed] between the 2 arms.

What did the safety profile of the combination look like?

Data from a prior phase 1 trial [NCT02071862] that examined telaglenastat alone in heavily pretreated patients demonstrated a very tolerable profile, with very few adverse effects [AEs] reported; these effects were mostly grade 1 or 2. [Common AEs included] nausea, fatigue, photophobia, a slight elevation in liver function tests, diarrhea, and rash, [which are] typical [toxicities that we see with] targeted agents. Overall, the agent was well tolerated, and had a low discontinuation rate.

In terms of the AEs in CANTATA, they were very comparable between the arms. Any-grade AEs [were reported in about 99% of patients] in both arms, [and they] were consistent with either agent when it is given alone. The notable grade 3 AEs were diarrhea and hypertension; these were driven mostly by cabozantinib. [In terms of the] discontinuation rate, 10% of patients discontinued therapy in the experimental arm vs 15% in the placebo arm, and [approximately 80% of patients] required a dose interruption or reduction of cabozantinib on both arms.

What are your thoughts on why the trial turned out to be negative?

This [trial] obviously [had] an unselected patient population; it [was] not based on biomarkers. Why did the telaglenastat plus cabozantinib combination not show superiority in terms of PFS compared with placebo plus cabozantinib? Was the partner, cabozantinib, not the correct partner? If we go back to the hypothesis, which is tumor metabolism, is blocking the glutamine pathway relevant in oncology? I do believe it is. There is a high expression of this enzyme in many tumor types, and there are strong preclinical data in vitro and in vivo to suggest that this is a relevant pathway in oncology and tumor metabolism. [However,] could another agent combined with telaglenastat show a positive result?

[Data from a previous phase 2] study, [ENTRATA; NCT03163667], were presented during the 2019 ESMO Congress. Here, everolimus was combined with telaglenastat and compared with placebo plus everolimus. [This was a] smaller study of 69 patients; it had a similar design, [but] a 2:1 randomization. In that study, the PFS was also the primary end point, and the medium PFS was doubled with telaglenastat plus everolimus in a very heavily pretreated patient population, at 3.8 months vs 1.9 months with placebo plus everolimus. [As such, in terms of] blocking glucose and glutamine, these 2 pathways are important in tumor metabolism; [these data proved that] the hypothesis was correct. However, maybe the CANTATA study was negative because cabozantinib may not have been the best partner for [telaglenastat].

Where should future efforts be focused with telaglenastat?

Thinking forward, [we could evaluate the regimen in] a more selected patient population with tumors that are more metabolically driven rather than unselected [patients with] clear cell RCC. It is important to mention that there is a phase 2 study [NCT04265534] combining telaglenastat with chemotherapy in patients with nonsquamous non–small cell lung cancer that are driven by a mutation. Therefore, maybe in that patient population that is biomarker selected, we will see positive results. [Additionally,] some other ideas are being formulated to see whether we can test the same combination in other rare tumors of the kidney.

Tannir N, Agarwal N, Porta C, et al. CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double-blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies. 

. 2021;39(supp 15):4501. doi:10.1200/JCO.2021.39.15_suppl.4501

“Telaglenastat/Cabozantinib Does Not Significantly Improve PFS in Metastatic RCC, But Future Directions Hold Promise”

The results of the phase 2 CANTATA trial indicate that the combination of telaglenastat/cabozantinib does not significantly improve PFS, however, telaglenastat might still prove effective in certain populations. 

Telaglenastat Plus Cabozantinib Fails to Improve PFS in Metastatic RCC, But Still Holds Promise 

The phase 3 MINDACT trial (NCT00433589) demonstrated that patients with early-stage breast cancer who have ultralow risk disease indicated by a 70-gene signature show superior survival outcomes.

At a median follow-up of 8.7 years, the 8-year distant metastasis-free interval (DMFI) rate in patients with ultralow-risk disease was 97.0% (95% CI, 95.8%-98.1%) vs 94.5% (95% CI, 93.6%-95.3%) in low-risk patients and 89.2% (95% CI, 87.9%-90.5%) in high-risk patients. The risk of distant metastases or death was significantly lower in ultralow-risk patients vs low-risk patients (Hazard ratio [HR], 0.65; 95% C, 0.45-0.94). Similarly, the risk was lower for low-risk patients, compared with high-risk patients (HR, 2.17; 95% CI, 1.68-2.80). Moreover, the 8-year breast cancer–specific survival (BCSS) rate was 99.6% (95% CI, 99.1%-100%) in patients with ultralow-risk disease, 98.2% (95% CI, 97.7%-98.7%) in those with low-risk disease, and 93.7% (95% CI, 92.6%-94.7%) in those with high-risk disease.

“Our results confirm previously published results of excellent survival in ultralow-risk patients in the largest cohort to date,” presenting author Josephine Lopes Cardozo, MD, a PhD candidate at the Netherlands Cancer Institute and medical fellow at the European Organization for Research and Treatment of Cancer, said during an oral presentation of the data. “As we know, especially in low-risk breast cancers, recurrences occur very late. Longer follow-up will reveal whether the excellent prognosis of ultralow-risk patients continues, as seen in other studies on ultralow-risk [disease].”

Since the 1990s, there has been an increase in the incidence of breast cancer, with a large increase in the incidence of small tumors, and almost no decrease in the incidence of large tumors, according to Lopes Cardozo. However, there has also been an increase in 10-year survival for patients with all stages of breast cancer, with the exception of stage IV disease. This increase in survival rates can be attributed to developments in adjuvant systemic treatment, mammographic screening, and improvements in local and regional treatments.

The 70-gene signature has demonstrated level 1 clinical utility in identifying patients with a preserved outcome when treated with adjuvant endocrine therapy and no chemotherapy, Lopes Cardozo said. Moreover, the 70-gene signature is able to identify patients who are at a low- or high-risk of distant recurrence within 5 years of breast cancer diagnosis. In 2017, a threshold for ultralow-risk disease was defined as a 100% BCSS rate at 15 years in independent validation cohorts of the 70-gene signature, she explained.

Two studies have demonstrated that tumors with a low- and ultralow-risk biology, according to the 70-gene signature, are overrepresented in cancers detected through screening. In one study, a cohort of patients were examined prior to the introduction of widespread screening (1984 to 1992) and compared with another cohort of patients who were examined after widespread screening was adopted (2004-2006). Results indicated that there was a significantly higher proportions of patients with low- and ultralow-risk tumors in the screened cohort vs the prior to the widespread introduction of screening cohort.

Similarly, in Dutch patients who were assessed on the MINDACT trial, a significantly higher rate of low- and ultralow-risk tumors were observed in patients with cancers detected through screening (69%; n = 754) compared with patients whose tumors were found in the intervals between 2 screening rounds (52%; n = 348).

Historically, patients with ultralow-risk tumors, as assessed by the 70-gene signature, have had excellent survival outcomes. In validation cohorts that were used to set the threshold for ultralow-risk tumors, 98% of patients received no adjuvant systemic treatment. Moreover, the 15-year BCSS was 100% for patients with ultralow-risk disease.

Additionally, another prior study analyzed a cohort from the historic STO-3 trial, which examined patients with lymph node–negative breast cancer smaller than 3 cm. Patients were randomized to receive either tamoxifen or no adjuvant systemic treatment. Among patients for whom a 70-gene signature could be performed, 339 received tamoxifen, while 313 received no adjuvant systemic treatment. Results indicated that patients in the cohort with ultralow risk tumors had excellent 20-year BCSS outcomes, with rates of 97% in those who received tamoxifen and 94% in those who received no adjuvant systemic treatment. However, the number of patients with ultralow-risk disease examined on both studies was notably small.

As such, investigators sought to assess survival outcomes in patients with an ultralow-risk tumor biology who were included in the MINDACT trial, as well as examine if the identification of an ultralow-risk patient subgroup by 70-gene signature could help to avoid overtreatment in early-stage breast cancer.

The MINDACT trial enrolled women aged 18 to 70 years old with operable invasive breast cancer and whose tumor size was a maximum of 5 cm. Additionally, patients enrolled on the study could have 0 to 3 positive lymph nodes. Patients with distant metastases were excluded from the trial.

Patients were stratified based on clinical risk by clinical-pathological characteristics and genomic risk based on the 70-gene signature.9 On the study, patients with concordant low-risk stratification received no adjuvant chemotherapy, while those with concordant high-risk stratification did receive chemotherapy. Additionally, the 2 study groups with discordant risk stratification were randomized to follow either the clinical or genomic risk stratification to receive chemotherapy or not, Lopes Cardozo added.

In total, 6693 patients were enrolled on the MINDACT trial. Of those patients, profiling revealed ultralow risk by 70-gene signature in 15% (n = 1000) of patients and 49% (n = 3295) of patients were clinically low risk. Among these patients, approximately 95% presented with hormone receptor (HR)–positive, HER2-negative disease vs 57% of high-risk patients (36%; n = 2398). Additionally, 76% to 85% of patients with low- or ultralow-risk disease received endocrine therapy only or no adjuvant systemic treatment, while 83% of high-risk patients received chemotherapy.

Among the subgroup of patients with ultralow-risk disease, the majority were older than 50 years of age (67%), lymph node-negative (80%), had tumors sized 2 cm or smaller (81%), had grade 1 or 2 disease (96%), and had HR-positive/HER2-negative subtyping (97%). Additionally, 16% of ultralow-risk patients received no adjuvant systemic treatment, 69% received endocrine therapy, and 14% received chemotherapy. Moreover, in terms of clinical risk, 741 of the ultralow risk patients had clinically low-risk tumors, while 259 had clinically high-risk tumors, defined as being larger in size, having a higher grade, and being lymph node positive.

In an assessment of DMFI in genomic ultralow-risk patients by clinical risk, those with clinically low-risk tumors had a slightly higher 8-year DMFI rate of 97.6% (95% CI, 96.4%-98.8%), vs 95.0% (95% CI, 92.3%-97.8%) in those with clinically high-risk tumors.

No statistically significant difference in 8-year BCSS rate was noted among genomic ultralow-risk patients, with the clinically low-risk group achieving a rate of 99.7% (95% CI, 99.3%-100%) and 99.2% (95% CI, 98.0%-100%) in the clinically high-risk group.

Additionally, in patients with ultralow-risk disease who received no adjuvant systemic treatment (n = 157), the 8-year DMFI rate was 97.8% (95% CI, 95.3%-100%), while it was 97.4% (95% CI, 96.1%-98.7%) in those who received endocrine therapy only (n = 685). Lastly, a rate of 94.9% (95% CI, 94.4%-98.7%) was reported in those who received chemotherapy with or without endocrine therapy (n = 144). Notably, 92% of patients who received chemotherapy had clinically high-risk disease.

“The clinical implications of this research are that we can confirm that the 70 gene signature can identify patients with an ultralow risk of recurrence, and that these patients could be candidates for further de-escalation of treatment, thus further reducing overtreatment, and the risk of [adverse] effects,” Lopes Cardozo concluded.

Cardozo J, Drukker C, Schmidt M, et al. Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. 

. 2021;39(15):500-500. doi:10.1200/JCO.2021.39.15_suppl.500

Autier P, Boniol M, Koechlin A, et al. Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. 

Piccart M, Veer L, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. 

. 2021;22(4):476-488. doi:10.1016/S1470-2045(21)00007-3

Veer L, Dai H, Vijver M, et al. Gene expression profiling predicts clinical outcome of breast cancer. 

. 2002;415(6871):530-6. doi:10.1038/415530a.

Delahaye L, Drukker C, Dreezen C, et al. A breast cancer gene signature for indolent disease. Breast Cancer Res Treat. 2017;164(2):461–466. doi:10.1007/s10549-017-4262-0

Esserman L, Shieh Y, Rutgers E, et al. Impact of mammographic screening on the detection of good and poor prognosis breast cancers. 

. 2011;130(3):725-34. doi:10.1007/s10549-011-1748-z

Drukker C, Tinteren H, Schmidt M, et al. Long-term impact of the 70-gene signature on breast cancer outcome. 

. 2014;143(3):587-92. doi:10.1007/s10549-013-2831-4

Esserman L, Yau C, Thompson C, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. 

. 2017;3(11):1503-1510. doi:10.1001/jamaoncol.2017.1261

Cardoso F, Veer L, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. 

. 2016; 375:717-729. doi:10.1056/NEJMoa1602253

“Ultralow Risk 70 gene Signature is Indicative of Excellent Survival Outcomes in Early Stage Breast Cancer.”


Regardless of clinical risk, the survival prognosis of patients with early-stage breast cancer is high amongst those who have ultralow risk disease indicated by a 70-gene signature. 



Ultralow Risk 70-Gene Promises Superior Survival Outcomes in Patients with Early-Stage Breast Cancer

The phase 2 ZUMA-3 trial (NCT02614066) demonstrated that heavily pretreated patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) had robust and durable responses from receiving single infusions of the CAR T-cell therapy, KTE-X19.

At a median follow-up of 16.4 months (range, 10.3-22.1), the complete response/complete response with incomplete blood count recovery (CR/CRi) rate was 70.9%, including a CR rate was 56.4%. Additionally, 31% of responding patients were in ongoing remission at data cutoff, without the need for subsequent allogeneic stem cell transplantation (ASCT) consolidation. Moreover, the median overall survival (OS) was 18.2 months for all patients treated on the study, and has not yet been reached in those who achieved a CR/CRi.

“The efficacy, rapid manufacturing, and manageable safety profile support the promising role of KTE-X19 to provide a long-term clinical benefit in adult patients with relapsed/refractory B-ALL,” Bijal Shah, MD, MS, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, said during aa presentation on the data.

Among adult patients with B-ALL, approximately 40% to 50% experience relapse following initial treatment, and prognoses remain poor.2,3 For patients with relapsed/refractory B-ALL, the 1-year OS rate is 26% after first salvage therapy and continues to decrease with each subsequent line of therapy thereafter.4 Additionally, while novel agents, such as blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa), have yielded positive outcomes in this patient population, median OS is still less than 8 months and is largely dependent on ASCT.4-8

In order to address the unmet needs within this patient population, the phase 1/2 ZUMA-3 trial was conceived to examine KTE-X19, an autologous anti–CD-19 CAR T-cell therapy that was approved by the FDA in July 202 for the treatment of patients with relapsed/refractory mantle cell lymphoma. Previously, the phase 1 ZUMA-3 trial demonstrated a manageable safety profile, with an overall CR/CRi rate of 83%. Moreover, the phase 1 portion of the study established the recommend phase 2 dose of KTE-X19 at 1x106 CAR T cell/kg10.

The phase 2 portion of the ZUMA-3 trial included the largest adult-only population of patients with relapsed/refractory B-ALL to date.

In total, 71 adult patients were enrolled on the phase 2 portion of the ZUMA-3 study. Patients needed to be 18 years old or older with relapsed/refractory B-ALL and bone marrow blasts of greater than 5%. Additionally, patients who had received prior treatment with blinatumomab were able to enroll.

Patients underwent conditioning chemotherapy with fludarabine at a dose of 25 mg/m2 on days -4, -3, and -2 prior to infusion, as well as with cyclophosphamide at a dose of 900 mg/m2 on day -2 prior to infusion. Then, patients went on to receive the infusion of KTE-X19 at a dose of 1x106 anti-CD19 CAR T cells/kg on day 0.

The primary end point for the study was CR/CRi by central assessment, with key secondary end points including minimal residual disease (MRD)–negativity rate, duration of response (DOR), relapse-free survival (RFS), OS, safety, and CAR T-cell levels in blood, and cytokine levels in serum.

Of the 71 patients enrolled on study, 57 went on to conditioning chemotherapy, and 55 went on to receive KTE-X19 infusion. The primary reasons for not proceeding to infusion included infection, thrombosis, and failing to meet eligibility. Moreover, safety and efficacy results were reported from the 55 patients who went on to receive infusion.

KTE-X19 was successfully manufactured for 92% of patients (n = 65/71). Moreover, the median time from leukapheresis to KTE-X19 manufacturing release was 13 days for patients in the United States, while it was 14.5 days for patients in Europe.

Among patients enrolled on the study, the median age was 40 years old (range, 19-84), and the majority were male (60%) with an ECOG performance status of 1 (71%). Additionally, 27% of patients were Philadelphia chromosome–positive and all had central nervous system–disease at baseline. Patients received a median of 2 prior therapies (range, 1-8) and 47% of patients had undergone 3 or more prior lines of therapy.

The majority of patients enrolled has relapsed on or were refractory to 2 or more prior systemic lines of treatment (78%), while 45% of patients had received prior treatment with blinatumomab, 22% received prior treatment with inotuzumab ozogamicin, and 42% had undergone prior ASCT. Moreover, the median rate of bone marrow blasts at screening was 65% (range, 5%-100%), while the median rate at preconditioning after bridging chemotherapy was 59% (range, 0%-98%).

For patients who achieved a CR/CRi, the median time to CR/CRi was 1.1 months (range, 0.85-2.99). Additionally, 10 patients in total, including 9 who had achieved a CR/Cri and 1 with blast-free hypoplastic or aplastic bone marrow, underwent ASCT at a median of 98 days (range, 60-207) following treatment with KTE-X19. Additionally, the minimal residual disease (MRD)-negativity rate was 97% in responders.

“Responses were largely consistent across subgroups, including those who were older, those who were more heavily pretreated, those who had undergone prior ASCT, … and those who were considered primary refractory,” Shah said. “The only group to show a lower response rate were those with a bone marrow blast burden greater than 75%.”

The median DOR was 12.8 months, with or without censoring patients at subsequent ASCT and as of data cutoff, 31% of the patients who achieved a CR or CRi had ongoing remissions without receiving subsequent ASCT.

Moreover, the median RFS was 11.6 months for patients who received KTE-X19, and 14.2 months for those who achieved a CR/CRi.

In terms of safety, the most common grade 3 or higher adverse effects (AEs) were anemia (49%) and pyrexia (36%). There were also 10 instances of grade 5 AEs reported, 4 of which were ALL; 2 were treatment-emergent from KTE-X19 and included brain herniation and septic shock; 3 occurred after initiation of another cancer treatment and included fungal pneumonia, sepsis, and respiratory failure; and 1 was pneumonia unrelated to treatment with KTE-X19.

There were not reported grade 5 events of cytokine release syndrome (CRS) or other neurological AEs. However, 24% of patients reported grade 3 or higher CRS, while 25% reported other grade 3 or higher neurological events. To treat these AEs, patients were given tocilizumab (Actemra; 80%), steroids (75%), and vasopressors (40%).

Higher levels of peak CAR T-cells were seen in patients with ongoing CR/CRi, followed by those who relapsed, and was lowest in those who did not achieve a CR or Cri. Moreover, levels were higher in patients who achieved CR/CRi and those who were MRD-negative. Peak CAR T-cell levels were also positively associated with grade 2 or higher CRS and grade 3 or higher neurological events. Moreover, the median time to peak CAR T-cells levels in the blood after infusion with KTE-X19 was 15 days (range, 7-32). In the 10 responders with evaluable samples at month 12, everyone had recovered peripheral B cells while 1 patients had detectable T cells.

1. Shah B, Ghobadi A, Oluwole O, et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor T-cell therapy, in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia. 

. 2021;39(15):7002-7002. doi:10.1200/JCO.2021.39.15_suppl.7002

2. Paul S, Kantarjian H, Jabbour E, et al. Adult acute lymphoblastic leukemia. 

. 2016;91(11):1645-1666. doi:10.1016/j.mayocp.2016.09.010.

3. Gökbuget N, Zugmaier G, Klinger M, et al. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. 

4. Topp M, Gökbuget N, Stein A, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. 

. 2015;16(1):P57-66.doi:10.1016/S1470-2045(14)71170-2

5. Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. 

. 2016;375:740-753. doi:10.1056/NEJMoa1509277

6. Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. 

. 2019.125(14):2474-2487. doi:10.1002/cncr.32116

7. DeAngelo D, Stock W, Stein A, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. 

 Adv. 2017; 1(15):1167-1180. doi:10.1182/bloodadvances.2016001925.

This article was originally published on Targeted Oncology as 

“Long-Term Clinical Benefit Potential Seen with KTE-X19 for Relapsed/Refractory B-ALL.”

A virtual presentation at the 2021 American Society of Clinical Oncology Annual Meeting suggested that patients with B-ALL benefit from single infusions of KTE-X19 (Tecartus). 



Patients with Relapsed/Refractory B-ALL Achieve Long-Term Clinical Benefit with KTE-X19

 mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens, according to data from a real-world retrospective analysis presented at the 2021 ASCO Annual Meeting.

Results, indicated that the median TOT in patients who received second-line cetuximab was 3.94 months (median interquartile range [mIQR], 3.51-4.40), while the median OS was 14.36 months (mIQR, 13.01-15.70).

Moreover, receiving second-line treatment with cetuximab plus FOLFIRI (median TOT = 4.43 months; mIQR, 3.71-5.36), having 

 wild-type status, and receiving second-line cetuximab following frontline capecitabine plus oxaliplatin (CAPOX), were all associated with a longer median TOT. Moreover, residing in the South region vs the Midwest of the United States was linked with a shorter median TOT.

Having a higher BMI was associated with a longer median OS (obese vs underweight HR, 0.46; 95% CI, 0.32-0.66), while receiving treatment with second-line cetuximab plus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was linked with a shorter median OS (10.97 months; mIQR, 5.55-14.06). Additionally, being older than 65 years was also linked with a shorter median OS (≥65 years vs <65 years; HR, 1.24; 95% CI 1.05-1.46).

Anti-epidermal growth factor receptor drugs are being increasingly utilized in later lines of therapy in patients with mCRC, but the real-world TOT and OS of patients who receive cetuximab in second-line setting has not been examined. As such, investigators set out to examine characteristics linked with TOT and OS using retrospective observational data.

Between January 2013 and August 2020, 1011 patients were selected from the nationwide Flatiron electronic health record database. Patients were included in the analysis if they had a mCRC diagnosis, received second-line treatment with a cetuximab-based regimen, and had progressed on oxaliplatin/irinotecan-based regimens in the frontline.

Investigators defined TOT as the time from start of cetuximab in the second line to the last date of evidence of administration. Moreover, end of treatment was defined if patients progressed to a third line of therapy or if they had a death record. Additionally, OS was calculated from index date to the date of death or censored to the last visit date available.

Among the 1011 patients included in the analysis, more than half were younger than 65 years (58%) and male (60%). Additionally, most patients had a median BMI of 26.6 kg/m², had previously received FOLFOX regimens in the first-line setting (61%), and received treatment in the community setting (96%). The most frequently used second-line treatment regimens were cetuximab plus FOLFIRI (46%) and cetuximab plus irinotecan (29%).

Gathirua-Mwangi W, Yang T, Khan T, et al. Real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in second line after failing irinotecan or oxaliplatin-based regimens. 

. 2021;39(suppl 15):e15568. doi:10.1200/JCO.2021.39.15_suppl.e15568

KRAS mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens.

Patient Characteristics Linked to Time on Treatment and Survival in Patients With mCRC Receiving Cetuximab

Patients with BRCA1/2-mutant, early HER2-negative breast cancer at a high risk of recurrence saw a clinically meaningful benefit 1 year after standard of care when treated with olaparib (Lynparza), according to data from the phase 3 OlympiA trial (NCT02032823).

Results from the multicenter, randomized, placebo-controlled trial, which were presented during a virtual press briefing ahead of the 

 indicated that after a median follow-up of 2.5 years, patients who received olaparib experienced a 42% reduction in invasive disease-free survival (iDFS), including local and metastatic recurrence of breast cancer, other new cancers, and death due to any cause, (Hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; 

 <.0001). Additionally, investigators noted a difference in 3-year iDFS rate between olaparib and placebo of 8.8% (95% CI, 4.5%-13.0%; stratified HR, 0.58; 99.5% CI, 0.41-0.82; 

“The OlympiA study is the first to report the benefits of [an adjuvant] PARP inhibitor for early forms of germline 

–mutation associated cancer,” presenting study author Andrew Tutt, MB, ChB, PhD, FMedSci, head of the Division of Breast Cancer Research, director of the Breast Cancer Now Toby Robins Research Centre, a clinician scientist with the Laboratory and Clinical Trials programme, and consultant clinical oncologist at the Institute of Cancer Research, said. “Patients who received olaparib after surgery and chemotherapy were more likely to be alive without cancer, [as well as] avoid metastasis than the patients who received placebo.”

Patients with HER2-negative early breast cancer who harbor a 

 mutation, which are present in approximately 5% of all breast cancers, are at a high risk of disease recurrence. Although outcomes have been positive for patients with these mutations who have received standard treatments such as surgery, radiotherapy, and chemotherapy, the risk of recurrence remains high for some patients. As such, additional novel targeted therapies are needed in order to reduce the risk of recurrence in this patient population.

Patients with BRCA1/2-mutant, early HER2-negative breast cancer at a high risk of recurrence saw a clinically meaningful benefit 1 year after standard of care when treated with olaparib.

Courtney Marabella