Rechallenging olaparib (Lynparza) as a maintenance therapy in heavily pretreated patients with relapsed ovarian cancer following response to platinum-based chemotherapy significantly improved progression-free survival (PFS), regardless of 

 status, according to data from the phase 3 OReO/ENGOT Ov-38 (NCT03106987) study presented during the 2021 ESMO Congress.

Data showed that the median PFS improved from 2.8 months in patients who received placebo to 4.3 months in those randomized to rechallenge with olaparib among the cohort of patients with 

-mutant ovarian cancer (HR, 0.57; 95% CI, 0.37-0.87; 

-mutant cohort, the median PFS improved similarly with olaparib rechallenge from 2.8 months in the placebo arm to 5.3 months in the olaparib arm (HR, 0.43; 95% CI, 0.26-0.71; 

The data are the first to demonstrate a benefit to PARP inhibitor rechallenge in patients with platinum-sensitive relapsed ovarian cancer, said Eric Pujade-Lauraine, MD, PhD, of ARCAGY-GINECO in Paris, France, in a virtual presentation during the meeting.

-mutant cohorts, a proportion of patients derived clinically relevant long-term benefit from maintenance olaparib rechallenge,” he said.

Although most patients with newly diagnosed or platinum-sensitive relapsed ovarian cancer achieve long-term responses to PARP inhibitors as maintenance therapy, the majority of them will relapse. It has been unknown whether patients who relapse on PARP inhibition will have a benefit from rechallenged PARP inhibitor therapy following responde to platinum-based chemotherapy.

OReO/ENGOT Ov-38 is a phase 3, randomized, double-blind trial that enrolled 220 patients with nonmucinous platinum-sensitive relapsed ovarian cancer who received 1 prior line of PARP inhibitor maintenance and were in response to their most recent platinum-based chemotherapy. Two cohorts were enrolled, a 

-mutant cohort (n = 108), both of which were randomized 2:1 to olaparib at 300 mg (or 250 mg if 300 mg was not previously tolerated) or placebo until progression.

Eligible patients must have had a complete response (CR) or partial response to their most recent platinum regimen or no evidence of disease after surgery without a rise in their CA-125 level. The 

-mutant cohort must have had prior PARP inhibitor exposure for at least 18 months after first-line chemotherapy, or at least 12 months after second-line or later chemotherapy. For the non–

-mutant cohort, prior PARP inhibitor exposure for at least 12 months after frontline chemotherapy or at least 6 months after second- or later-line chemotherapy was required.

Patients were stratified by prior bevacizumab (Avastin) and 3 or fewer or at least 4 prior lines of platinum-based chemotherapy. The primary end point was investigator-assessed PFS; secondary end points were time to RECIST/CA-125 progression or death, time to first and second subsequent therapy or death, time to treatment discontinuation or death, overall survival, health-related quality of life, and safety.

-mutant cohort, the median age was 58.5 years (range, 37-80) in the olaparib arm and 61.5 years (range, 44-87) in the placebo arm. Forty-two percent of patients in each arm had 3 prior lines of any chemotherapy, and 23% and 21% in the olaparib and placebo arms, respectively, had exposure to more than 4 prior lines. Thirty-five percent of the olaparib arm and 42% of the placebo arm had exposure to more than 4 prior lines of platinum-based chemotherapy. The best response to platinum-based chemotherapy prior to study entry was a CR in 20% and 34% of the olaparib and placebo arms, respectively.

-mutant cohort, the median age was 66.5 years (range, 29-81) in the olaparib arm and 62.5 years (range, 43-77) in the placebo arm. Twenty-eight percent and 22%, respectively, had more than 4 lines of any prior chemotherapy, and 32% and 31%, respectively, had at least 4 prior lines of platinum-based chemotherapy. Best response to platinum-based chemotherapy prior to study entry was a CR in 26% of the olaparib group and 31% of the placebo group.

The median duration range of prior PARP inhibitor therapy was 18.3 to 21.2 months in the 

-mutant cohort and 12.4 to 12.6 months in the non–

-mutant cohort. Sixty-one percent of the 

-mutant cohort had a duration of prior PARP inhibitor exposure of at least 18 months, and 53% to 57% of the non–

-mutant cohort had a duration of prior PARP inhibitor exposure of at least 12 months.

-mutant cohort was olaparib (91% vs 21.5%, respectively), niraparib (Zejula; 4.5% vs 61%), rucaparib (Rubraca; 3% vs 13.5%), veliparib (0% vs 2%), blinded therapy (0% vs 3.5%), and placebo (1.5% in each).

Homologous recombination deficiency (HRD) status was positive in about 40% of the non–

-mutant cohort, with HRD status unknown in up to one quarter of patients in this cohort.

-mutant cohort, treatment is ongoing in 9% of patients on the olaparib arm and 3% of the placebo arm; in the non–

-mutant cohort, these percentages are 29% and 17%, respectively. About 60% of patients on the 

-mutant cohort discontinued the study, 90% of which were due to death. Twenty-eight percent of those in the non–

-mutant cohort discontinued, with 67% (olaparib arm) and 73% (placebo arm) discontinuing due to death.

“A proportion of patients derived long-term benefit in the olaparib arm,” said Pujade-Lauraine, as the PFS rates in the 

-mutant cohort at 12 months after randomization were 19% in the olaparib arm vs 0% in the placebo arm.

-mutant cohort, “long-term benefit was again observed—14% of patients in the olaparib arm being free of disease progression [at 12 months] vs 0% in the placebo arm,” he added. In exploratory analyses, the benefit of olaparib in the non–

-mutant cohort appeared consistent, irrespective of HRD status.

In both cohorts, the PFS benefit to olaparib was observed across subgroups, and was irrespective of HRD status. No new safety signals were observed and the rate of discontinuations due to adverse events was low, said Pujade-Lauraine.

Clare L. Scott, MBBS, PhD, chair of Gynecological Cancer at University of Melbourne, Australia, who served as a discussant on the abstract, said that the results from OReO/ENGOT Ov-38 provide some rules to identify patients who would benefit based on prior PARP inhibitor exposure.

“All clinical groups appear to benefit except for patients who had a short time on treatment prior to coming on to study, but really we need to define the molecular groups who benefit from alternative therapies or combination PARP inhibitor therapies,” Scott said.

Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): phase IIIb OReO/ENGOT Ov-38 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA33.

Articles

Rechallenge with maintenance olaparib following response to platinum-based chemotherapy significantly improved PFS in heavily pretreated patients with relapsed ovarian cancer.

Rechallenge With Olaparib Maintenance Improves PFS in Heavily Pretreated Ovarian Cancer

Encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) demonstrated longer maintenance of quality of life (QoL) on patient-reported assessments over current standard of care in the treatment of patients with BRAF V600E-mutant metastatic colorectal cancer.

In the phase III BEACON CRC study, both the triplet and doublet regimens reduced the risk of QoL deterioration by more than 40% by multiple QoL assessment instruments compared with the control regimen, said Scott Kopetz, MD, PhD, at the 2020 Gastrointestinal (GI) Cancers Symposium.

In addition, updated overall survival (OS) results from the study showed additional improvement in median OS of 1 month, to 9.3 months, in the doublet arm (encorafenib plus cetuximab), with a median OS follow-up of almost 13 months.1

As reported previously and published in the New England Journal of Medicine, after a median follow-up of 7.8 months, the median OS was 9.0 months in the triplet arm versus 5.4 months in the control group (HR, 0.52; 95% CI, 0.39-0.70; P <.001). The median OS in the doublet arm was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; P <.001).2

Updated OS results showed median OS of 9.3 months with either the triplet or doublet compared with 5.9 months in the control arm, said Kopetz , professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston. The overall response rates at the updated analysis were 26% with the triplet, 20% with the doublet, and 2% in the control arm. No new safety signals were identified in the updated analysis.

BEACON CRC was an international open-label phase III trial that enrolled 665 patients with BRAF V600E—mutated metastatic colorectal cancer whose disease had progressed after 1 or 2 prior regimens. After a safety lead-in, patients were randomly assigned in a 1:1:1 ratio to the targeted therapy triplet of encorafenib, binimetinib, and cetuximab; the targeted therapy doublet of encorafenib and cetuximab; or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).

Relative dose intensity was high in each arm. Dose intensity in the triplet arm was 91% for encorafenib, 87% for binimetinib, and 91% for cetuximab. In the doublet arm, it was 98% for encorafenib and 93% for cetuximab. For the control arm, it was 74% to 85%. The rates of adverse events (AEs), grade 3/4 AEs, and serious AEs were comparable across the 3 arms.

“We recognized that safety doesn’t always capture the patient experience and that is the rational for incorporating QoL metrics into the study. This is an important component that really helps to understand the patient experience and complements the clinical efficacy endpoint,” said Kopetz.

The QoL assessments, a secondary endpoint from BEACON CRC, were reported at the GI Symposium. Four QoL instruments were used: EORTC QLQ 30 (EORTC QOL Questionnaire), FACT C (Functional Assessment of Cancer Therapy Colon Cancer), EQ 5D 5L (EuroQoL 5D 5L), and PGIC (Patient Global Impression of Change). These instruments were assessed at screening/baseline, at day 1 of every treatment cycle, at end of treatment, and the 30-day safety follow-up visit.

Compliance with each of the tools was high across all arms: 85% to 97% with the EORTC QLQ 30, FACT C, and EQ 5D 5L instruments, and 67% to 89% with the PGIC. The primary assessment in the EORTC QLQ 30, FACT C, and EQ 5D 5L instruments scales was the time to definitive 10% deterioration in scores.

The median time to deterioration (TTD) in the EORTC QLQ 30 was 4.96 months in the triplet arm vs. 2.2 months in the control arm, corresponding to a delay in deterioration by 45% with the triplet (HR, 0.55; 95% CI, 0.43-0.70). In the doublet arm, median TTD on this same scale was 4.6 months, corresponding to a 46% delay in deterioration compared with controls (HR, 0.54; 95% CI, 0.43-0.69).

The median TTD in the FACT C scale was 5.65 months in the triplet arm versus 2.0 months in the control arm, for a reduction in risk of 52% (HR, 0.48; 95% CI, 0.38-0.62). In the doublet arm, the median TTD on the FACT C was 5.36 months, translating to a 54% reduction versus control (HR, 0.46; 95% CI, 0.36-0.59).

On the EQ 5D 5L, the median TTD was 5.59 months in the triple arm, 5.36 months in the doublet arm, and 2.37 months in the controls, corresponding to reductions in risk of 51% in the triplet arm versus controls (HR, 0.49; 95% CI, 0.38-0.63) and 51% in the doublet arm compared with the control arm (HR, 0.49; 95% CI, 0.39-0.63).

Some 53% of patients randomized to the triplet and 58% randomized to the doublet had at least a minimal improvement in symptoms on the PGIC compared with only 36% of the controls.

Published data showed that discontinuation of therapy due to AEs occurred in 7%, 8%, and 11% of patients in the triplet, doublet, and controls arms, respectively. The most common grade 3/4 AEs observed in the triplet arm were diarrhea (11% vs 3% in the doublet arm and 10% in the control arm), abdominal pain (6% vs 3% in the doublet arm and 5% in the control), and nausea (5%, <1%, and 2%, in the 3 arms, respectively).

“On the basis of these results, the decision was made not to submit binimetinib to the FDA, and the doublet of encorafenib and cetuximab is under review,” Kopetz said.

1. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 8.       

2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632-1643.

This article originally appeared on OncLive as, "

Triplet and Doublet Regimens Outperform Standard of Care on Survival, QoL in BRAF+ CRC

Combination Therapy Bests Standard of Care in BRAF+ CRC

Steroid use while cytokine release syndrome (CRS) and neurologic toxicities are at grade 1, instead of waiting until grade 3, reduces the rate of CAR T-cell treatment—related CRS and neurologic events.

In a cohort of patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL) who were treated with axicabtagene ciloleucel (axi-cel; Yescarta) who received early corticosteroid and tocilizumab as part of a nonrandomized expansion arm of the ZUMA-1 study, only 2% experienced grade ≥3 CRS and only 17% experienced grade ≥3 neurologic events, compared with 13% and 28%,

 respectively, in patients who started them later, said lead study author Max S. Topp, MD, at the 2019 ASH Annual Meeting.

“Earlier steroid intervention has the potential to improve the risk/benefit profile of CAR T-cell therapy with axi-cel,” said Topp, professor of oncology, University Hospital of Wuerzburg, Germany. “This intervention led to a lower total cumulative steroid usage in this cohort with no impact on expansion of T cells. It reduced markers of inflammatory response, had no impact on ongoing response with or without adjustment for tumor burden at a median follow-up of 8.7 months.”

ZUMA-1 was a pivotal multicenter single-arm phase I/II study in which axi-cel treatment in patients with R/R LBCL induced an objective response rate of 83%, with a 58% rate of complete response, a median overall survival (OS) of 25.8 months, and a 3-year OS rate of 47%.2 In cohorts 1 and 2 of ZUMA-1, grade ≥ 3 CRS and neurologic events occurred in 11% and 32% of patients, respectively.

 evaluated the use of prophylactic tocilizumab on day 2, which appeared to decrease rates of grade ≥3 CRS but not rates of grade ≥3 neurologic events.3 An additional safety cohort (cohort 4) was added to evaluate the effect of earlier corticosteroid use on the rates of these adverse events.

Cohorts 1 and 2 of the phase 2 portion of ZUMA-1 included 101 patients. Cohort 1 enrolled 77 patients with R/R diffuse LBCL; cohort 2 enrolled 24 patients with R/R primary mediastinal B cell lymphoma/transformed follicular lymphoma. Cohort 4 enrolled 41 patients with R/R LBCL. Optional bridging therapy was allowed in cohort 

In cohorts 1 plus 2, neither corticosteroids nor tocilizumab were given with grade-1 CRS or neurologic events; both were given with grade-2 CRS only if patients had comorbidities or were older. Tocilizumab was administered to all patients with grade ≥3 CRS. Patients with grade ≥2 neurologic events received tocilizumab but not corticosteroids. Corticosteroids were given with grade-3 neurologic events only if no improvement was observed with tocilizumab. Both tocilizumab and corticosteroids were used in the case of grade-4 CRS or neurologic events.

Patients in cohort 4 received early steroid intervention starting at grade 1 neurologic events and at grade 1 CRS when no improvement was observed after 3 days of supportive care.

At baseline, 57% of patients in cohorts 1 plus 2 had stage IV disease versus 46% in cohort 4. About two-thirds (65%) of patients in cohorts 1 and 2 had progressive disease to most recent chemotherapy, compared with 37% in cohort 4.  Patients enrolled in cohort 4 had a lower median tumor burden by sum of product diameters and lower pretreatment serum LDH level compared with cohorts 1 plus 2. Median tumor burden was 3273 mm2 in cohort 1 plus 2 versus 2100 mm2 cohort 4, and the median levels of serum LDH  were 356 and 262 U/L, respectively. The median ferritin level was 786 ng/mL in the combined cohort 1 plus 2 versus 393 ng/mL in cohort 4.

The rates of CRS of any grade were 93% in the combined cohorts 1 and 2 and in cohort 4. The median time to onset of CRS was 2 days in each cohort and the median duration of CRS was 8 days in cohort 1 plus 2 versus 7 days in cohort 4.

The rates of neurologic events of any grade were 64% in cohort 1 plus 2 and 61% in cohort 4. The median duration of neurologic events was 12 days and 9 days, respectively. In patients with tumor burden above the median, the rates of grade ≥3 CRS and neurologic events was reduced from 6% and 20%, respectively, in cohort 1 plus 2 to 1% and 4%, respectively, with earlier use of corticosteroids and tocilizumab in cohort 4.

The ORR in cohort 4 was 73%, with a CR rate of 51%. More than half (54%) of patients in cohort 4 remained in ongoing response with at least 6 months of follow-up, compared with a 44% ongoing response rate at the primary analysis of cohort 1 plus 2 (also with ≥6 months of follow-up). Responses were comparable between cohorts when evaluated by tumor burden. Median duration of response was 8.9 months in cohort 4, which is consistent with that observed at the primary analysis of cohorts 1 plus 2 (8.1 months).

“By using early onward steroids, we could lower the amount of steroids that were actually given over the clinical trial,” said Topp. Some 85% of patients in cohort 1 plus 2 received at least 5 doses of steroids compared with only 43% of patients in cohort 4. The median cumulative steroid dose was reduced from 5451 mg in cohort 1 plus 2 to 939 mg in cohort 4.

Early steroid use had no impact on CAR T-cell expansion; the overall peak number of CAR T cells and the area under the curve were similar between cohort 1 plus 2 and cohort 4, said Topp. “Altogether, giving steroids [early] had a positive impact on the inflammatory environment in these patients,” as inflammatory serum cytokines associated with CAR T-cell—related toxicity were reduced in cohort 4, he said.

1. Topp M, Van Meerten TV, Houot R, et al. Earlier steroid use with axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refractory large B cell lymphoma. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 243. bit.ly/2qCnvXm.

2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7.

3. Topp MS, van Meerten T, Wermke M, et al. Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). J Clin Oncol. 2019;37(suppl 15; abstr 7558). doi: 10.1200/JCO.2019.37.15_suppl.7558.

Early Steroid Use Reduces Risk of Cytokine Release Syndrome With Axi-Cel

Steroid use while cytokine release syndrome (CRS) and neurologic toxicities are at grade 1, instead of waiting until grade 3, reduces the rate of CAR T-cell treatment–related CRS and neurologic events.


Early Steroid Use Reduces Cytokine Release Syndrome Risk With Axi-Cel Treatment

Adding the investigational glutaminase inhibitor telaglenastat to everolimus extends progression-free survival (PFS) compared with everolimus alone in patients with heavily pretreated advanced renal cell carcinoma (RCC), according to findings from the phase II ENTRATA study presented at the 2019 ESMO Congress.

In the randomized, double-blind ENTRATA study, the median PFS was 3.8 months in the telaglenastat plus everolimus arm compared with 1.9 months in the placebo plus everolimus arm (HR, 0.64; 95% CI, 0.34-1.20; one-sided P = .079). The improvement in median PFS with the addition of telaglenastat met the prespecified threshold for achieving the primary endpoint (investigator-assessed PFS), which was set at a one-sided P value of 0.2.

“The ENTRATA study supports proof of concept for telaglenastat and supports glutaminase inhibition as a new therapeutic strategy for metastatic RCC for further study,” said study investigator Chung-Han Lee, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center.

Increased glutamine and glucose metabolism supports tumor cell growth and proliferation. In tumors, cells undergo a metabolic shift in which growth factors drive abnormal glucose metabolism, known as the Warburg effect, which deprives the TCA cycle of key metabolites. “To compensate for this metabolic shift, glutamine metabolism is increased to sustain the TCA cycle for growth and proliferation,” said Lee.

Telaglenastat is an oral inhibitor of glutaminase, the key enzyme for conversion of glutamine to glutamate. In preclinical studies, telaglenastat in combination with the mTOR inhibitor everolimus inhibited both glucose and glutamine metabolic pathways and demonstrated synergistic antiproliferative activity. In mouse xenograft models, the combination enhanced the antitumor activity of everolimus.

A phase Ib study of 24 patients with metastatic RCC who had a median of 2 prior lines of therapy showed that the combination of telaglenastat and everolimus was associated with a disease control rate of 92% and a median PFS of 5.8 months, “which compared favorably to historical controls,” Lee said.

Patients with advanced clear cell RCC who had been treated with ≥2 prior lines of systemic therapy, including at least 1 VEGF receptor—targeted TKI, were eligible for ENTRATA. They were randomized in a 2:1 ratio to telaglenastat at 800 mg twice daily plus everolimus at 10 mg/day, or placebo plus everolimus. Patients with treated or stable brain metastases were allowed into the study. Prior mTOR inhibitor therapy was not permitted.

The 69 patients enrolled were heavily pretreated with a median of 3 prior lines of therapy, including 70% who received ≥2 prior TKIs. Median patient age was about 65 years, and 80% (telaglenastat arm) and 87% (placebo arm) were male. Some 68% of patients had an intermediate/poor MSKCC prognostic score. Some 91% in the telaglenastat arm and 83% in the placebo arm received prior PD-1/PD-L1 inhibitor therapy. “Patients had multiple sites of disease, with one-third of patients having bone metastases,” Lee said.

Subgroup analysis by age, sex, race, performance status, number of prior TKIs, MSKCC risk stratification, and prior PD-1/PD-L1-directed therapy did not identify any subgroups with disproportionate benefit, Lee said. “However, the trial was not powered to detect any differences within these subgroups.”

Best tumor response in the telaglenastat/everolimus arm was a partial response in 2.2% and stable disease in 56.5%. in the placebo/everolimus arm, there were no objective responses and best response was stable disease in 47.8%. The secondary endpoint of overall survival is not yet mature.

The rate of treatment-emergent adverse events leading to treatment discontinuation was similar between the arms: 28.3% in the telaglenastat/everolimus and 30.4% in the placebo/everolimus arm. Dose interruption or reduction of any drug due to adverse events occurred in 76.1% of patients randomized to telaglenastat/everolimus compared with 60.9% of those randomized to placebo/everolimus. Grade ≥3 adverse events occurred in 80% of patients in the telaglenastat plus everolimus arm versus 61% in the everolimus plus placebo arm. The most frequently reported grade ≥3 adverse events in the treatment versus control arms, respectively, were anemia (17% vs 17%) and fatigue (4% vs 9%).

Currently ongoing is the CANTATA &#8239;study (NCT03428217), which is a global, randomized, double-blind phase II study comparing telaglenastat in combination with cabozantinib versus placebo with cabozantinib in patients with advanced or metastatic renal cell carcinoma.

Motzer RJ, Lee C-H, Emamekhoo H, et al. ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (tela; CB-839) + everolimus (E) vs. placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA54.

Addition of Telaglenastat to Everolimus Extends Survival in Metastatic RCC

A numerical improvement in overall survival (OS) was realized with the addition of atezolizumab (Tecentriq) to ado-trastuzumab emtansine (T-DM1; Kadcyla) compared with T-DM1 alone in a second planned OS analysis of the phase II KATE2 trial, which was conducted in patients with previously treated HER2+ advanced breast cancer.

Further, the data suggest an OS benefit with atezolizumab plus T-DM1 in patients with PD-L1 expression in immune cells, with a 1-year survival rate of 94%, compared with 88% in the patients randomized to T-DM1 without atezolizumab, reported Leisha A. Emens, MD, PhD,  at the 2019 ESMO Congress.

The numerical advantage of atezolizumab did not translate into a significant effect in either the intent-to-treat (ITT) population or the subgroup of patients with PD-L1 expression in immune cells, however, as the 95% confidence intervals crossed 1.0 in both analyses. Thus, the findings should be considered hypothesis-generating, said Emens, co-leader of the Hillman Cancer Immunology and Immunotherapy Program, University of Pittsburgh.

“Based on these results, we believe that further study of HER2-targeted agents with atezolizumab in previously treated HER2-positive, PD-L1 immune cell—positive advanced breast cancer is warranted,” added Emens.

In the ITT population, median OS was not estimable in either treatment group after a median follow-up of 19.0 months in the atezolizumab/T-DM1 arm and 18.2 months in the placebo/T-DM1 arm (stratified HR, 0.74 favoring atezolizumab/T-DM1; 95% CI, 0.42-1.30). The 1-year OS rates were similar (89.1% and 89.0%) in the 2 arms, respectively.

In the patients who were positive for PD-L1 in their immune cells (IC 1/2/3), median OS was not estimable in either arm (stratified HR, 0.55 favoring atezolizumab/T-DM1; 95% CI, 0.22-1.38).

There was no numerical advantage to adding atezolizumab in patients who were PD-L1 immune cell-negative. In this group, median OS was not estimable with either treatment assignment (stratified HR, 0.88; 95% CI 0.43-1.80), and the 1-year survival rates were 85.1% in the atezolizumab/T-DM1 arm and 89.7% in the placebo/T-DM1 arm.

T-DM1 is indicated for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. In addition to having cytotoxic activity, T-DM1 may potentiate tumor immunity, said Emens.

In the randomized phase II KATE2 study, there was no significant difference in progression-free survival (PFS), the primary endpoint, in the overall population of patients with HER2-positive advanced breast cancer who were treated with atezolizumab plus T-DM1 versus placebo plus T-DM1 (median PFS: 8.2 vs 6.8 months; stratified HR, 0.82; 95% CI 0.55-1.23). PFS, however, was numerically greater with the combination in an exploratory analysis of a subgroup of patients who had PD-L1 expression in immune cells (median PFS: 8.5 vs 4.1 months; stratified HR, 0.60; 95% CI 0.32-1.11), she noted.

Patients eligible for KATE2 had HER2-positive advanced breast cancer treated previously with trastuzumab (Herceptin) and a taxane, and progressed on treatment for metastatic disease or within 6 months of completing adjuvant therapy. A total of 202 patients were randomized 2:1 to atezolizumab at 1200 mg plus T-DM1 at 3.6 mg/kg, both given every 3 weeks, or T-DM1 plus placebo. Therapy was continued until loss of clinical benefit or development of intolerable toxicity. PD-L1 status (IC0 [<1%] vs IC1/2/3 [≥1%]) was 1 of the stratification factors.

In the atezolizumab/T-DM1 arm (n = 133), 43% had PD-L1&shy;—positive disease, compared with 39% in the placebo/T-DM1 arm (n = 69). More patients in the placebo/T-DM1 arm had an ECOG performance status of 1 (41%) than in the atezolizumab/T-DM1 arm (29%). Otherwise, baseline demographics were well balanced between the 2 groups.

As of the data cutoff for the OS analysis (December 11, 2018), 61% of patients who received immunotherapy with T-DM1 remained on study, compared with 51% of the placebo/T-DM1 group. Nearly half (48%) of the placebo/T-DM1 arm discontinued the study due to either death or withdrawal by the patient, compared with 38% in the atezolizumab/T-DM1 arm.

“Other biomarkers of T cell activation and quantity were enriched specifically in the PD-L1 immune cell&shy;—positive group,” said Emens. Additional biomarkers included PD-L1 mRNA expression, CD8 mRNA expression, T effector gene signature, and stromal tumor infiltrating lymphocytes (TILs). The median level of stromal TILs was 5%. “Patients who had high levels of stromal TILs [greater than the median] had much higher levels of PD-L1 expression,” she said.

OS was analyzed by the aforementioned immune biomarker subgroups. “The association of these other immune biomarkers was consistent with the PD-L1 immune cell-positive subgroup data,” said Emens. “The biggest difference between the placebo and atezolizumab arm relates to stromal TILs, with high levels predicting benefit with the addition of atezolizumab to T-DM1.”

The rate of grade ≥3 adverse events (AEs) was greater in the atezolizumab arm than the placebo arm (53% vs 45%). Specifically, grade ≥3 AEs that were more common in the atezolizumab/T-DM1 group were thrombocytopenia (13% vs 4%), anemia (8% vs 0%), an increase in the level of aspartate aminotransferase (9% vs 3%), and an increase in the level of alanine aminotransferase (6% vs 3%). More patients in the placebo/T-DM1 group experienced grade ≥3 urinary tract infection (4% vs 1%) and grade ≥3 abdominal pain (4% vs 1%).

The rate of grade 5 AEs was 1.5% in each arm. Serious AEs were recorded in 36% and 21%, respectively, and AEs leading to discontinuation of any study treatment occurred in 29% and 15%, respectively.

The most common immune-related AEs were rash, hypothyroidism, and pancreatitis. The only 2 immune-related grade ≥3 AEs observed in the atezolizumab arm were 2 cases of rash. One patient in the placebo arm had grade ≥3 pancreatitis.

KATE2 should be considered a proof of concept trial, as only 84 patients with PD-L1&shy;—positive tumors enrolled, said the invited discussant, Giampaolo Bianchini, MD, head of the Breast Cancer Group—Medical Oncology at Ospedale San Raffaele, Milan, Italy.

“The small sample size does not allow a reliable estimate of the effect size of any endpoint,” said Bianchini. “Despite the trial limitations, the qualitative effect consistently seen in all clinical endpoints [overall response rate, PFS, OS] in PD-L1—positive tumors, defined by the SP142 score on immune cells [≥1%], provides a strong and robust signal supporting the investigation of immune checkpoint inhibitors in HER2-positive breast cancer. Many trials are ongoing in the early setting and the advanced setting.”

Emens LA, Esteva F, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract 305O.

Atezolizumab, along with T-DM1, showed benefit for a subgroup of patients with breast cancer.

Atezolizumab Plus T-DM1 Improves Overall Survival in Breast Cancer Subgroup

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) induced responses in nearly half of patients with 

 V600E—mutated biliary tract cancer (BTC) who participated in a phase II basket trial that enrolled patients with 

Results of the ROAR trial, which were presented during the 

 inhibitor combination was associated with an overall response rate (ORR) of 42% by investigator assessment, a median progression-free survival (PFS) of 9.2 months (95% CI, 5.4-10.1), and a median overall survival (OS) of 11.7 months (95% CI, 7.5-17.7) in the BTC cohort of the study, said Zev Wainberg, MD, co-director of the 

 Program at the University of California, Los Angeles. This efficacy is comparable with that obtained with first-line chemotherapy, comprising of gemcitabine and cisplatin.

“These results represent the first prospectively analyzed cohort of patients with 

 V600E-mutated BTC treated with a combination of BRAF and MEK inhibition,” he said. “

 V600 is one of several actionable driver mutations in this disease, and should be considered for routine testing in patients with BTCs.”

The combination “should be considered a meaningful therapeutic option” for patients with 

mutations have been identified in 5% to 7% of patients with BTC, primarily in the cohort with intrahepatic disease, he noted. The dabrafenib/trametinib combination has previously demonstrated efficacy in other 

-mutated cancers, including melanoma in the adjuvant and metastatic settings, non—small cell lung cancer, and anaplastic thyroid cancer.

ROAR also demonstrated the heterogeneous genetic backgrounds of BTC tumors that were “consistent with other reports in this tumor type,” he said.

Most patients with BTC present with advanced disease, and the 5-year survival rate is approximately 15%, said Wainberg. Beyond surgical resection, the standard of care includes chemotherapy with gemcitabine and cisplatin, which is associated with a PFS of 8.0 months and a median OS of 11.7 months.

ROAR is open-label, nonrandomized, multicenter study that enrolled patients with rare cancers that harbor 

 V600E mutations. The data presented at the 2019 Gastrointestinal Cancers Symposium were from the BTC cohort that included 35 patients. Only patients with histologically confirmed advanced or metastatic disease and no available standard treatment options were eligible for enrollment.

Treatment options for BTC after first-line therapy are not well defined. The median PFS in second-line BTC is <5 months. Activating 

 V600E mutations have been reported in up to 20% of BTCs.

The median age in the BTC cohort of ROAR was 57 years. Ninety-seven percent of patients had an ECOG performance status of 0 or 1. The predominant histology was adenocarcinoma, which was present in 74% of patients. All 35 patients had measurable disease at screening, and 74% of patients had stage III disease at enrollment. Their time since diagnosis was a median of 1.1 years. Some 80% had received ≥2 lines of prior systemic therapy, with 100% receiving prior gemcitabine and 63% prior cisplatin. Some 57% of patients had undergone surgery and 11% received radiation.

The median duration of exposure to dabrafenib plus trametinib was 6 months (range, 2-32 months) and 86% were on the study medications for >3 months. Twelve patients (34%) were continuing treatment with each agent at the time of data analysis. Sixty percent discontinued treatment with dabrafenib and 60% with trametinib because of disease progression. Twenty-two (63%) patients required dose interruption of dabrafenib and 21 (60%) required dose interruption of trametinib.

Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily on a continuous basis. Treatment was continued until unacceptable toxicity, disease progression, or death, and the primary endpoint was investigator-assessed ORR by RECIST v1.1. Secondary endpoints included PFS, duration of response (DOR), OS, and safety.

In the intent-to-treat/evaluable population (n = 33), with a median duration of follow-up of 8 months, the ORR was 42% by investigator assessment and 36% by independent review. All responses were partial responses (PRs). The stable disease (SD) rate was 45% by investigator assessment and 39% by independent review.

“Nearly every patient had some tumor reduction, with only 4 patients having progression of disease as their best response,” said Wainberg.

The investigator-assessed DOR at 6 months was 66%; 7 of 14 patients who achieved a PR had a duration of response >6 months and 5 patients had a response that was ongoing at data cutoff. Many of the patients who achieved stable disease but didn’t achieve a PR still had durable clinical benefit, he said.

Sixteen baseline tissue samples were successfully analyzed by targeted next-generation sequencing of 570 cancer-specific genes. “There were a number of genetic alterations seen in these patients, both mutations and amplifications, and there’s little in common between them,” supporting the diverse molecular phenotype, he said. Copy-number variant (CNV) analysis demonstrated loss of 

 as the most common finding, which was identified in 6 of 11 (55%) patients with any CNV.

Molecular analyses also demonstrated low mutational burden, consistent with other reports in this tumor type. All patients had <6 mutations/megabase. Correlative analysis of pathway signatures showed that gene expression levels of MAPK pathway members were higher in 2 patients with a best overall response of progressive disease compared with patients with a best overall response of stable disease.

Of the 35 patients in the BTC cohort, 11 received at least 1 posttreatment therapy, including chemotherapy in 20%, surgery in 14%, small molecule targeted therapies in 11%, 

 in 6%, biologic therapy in 6%, and radiotherapy in 3%. The median time from study discontinuation to the start of subsequent treatment was 6.6 weeks.

All-cause grade 3/4 adverse events (AEs) were reported in 57% of patients. The most frequent treatment-related AEs were pyrexia (40%), rash (29%), nausea (23%), diarrhea (23%), fatigue (23%), and chills (20%).

Wainberg ZA, Lassen UN, Elez E, et al. Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E—mutated biliary tract cancer (BTC): a cohort of the ROAR basket trial. In: Proceedings from the 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 187.

Dabrafenib/Trametinib Combo Induces High Responses in BRAF V600E-Mutant Biliary Tract Cancer

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) induced responses in nearly half of patients with BRAF V600E–mutated biliary tract cancer (BTC) who participated in a phase II basket trial that enrolled patients with BRAF V600E–mutated rare cancers.

combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux)

 V600E-mutant metastatic colorectal cancer, according to preliminary efficacy findings from the safety lead-in (SLI) phase of the 

. Updated results from 30 patients showed an estimated median progression-free survival (PFS) of 8.0 months and an estimated median overall survival (OS) of 15.3 months with a median duration of follow-up of 18.2 months,

The overall response rate (ORR) was 48% by local assessment, with 3 patients achieving a complete response (CR). Up to 15% of patients with metastatic colorectal cancer have 

 V600E mutations, which confer poor prognosis.

“We know that these patients have very poor survival; their median survival from the diagnosis is about 12 months,” said Kopetz, associate professor, Department of 

 Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, Texas. “The ORR of 48% is substantially better than historic controls, and encouraging that our OS is a median of 15 months with reasonably mature data. This is encouraging because these were patients who were received either second- or third-line treatment, and we’re seeing survivals that would exceed even what a first-line population would expect. This sets the stage for the phase III BEACON CRC results.”

Standards of care, generally with a cetuximab-based regimen, have historically demonstrated ORRs <10%, median PFS rates of about 2 months, and median OS rates of only 4 to 6 months, he noted.

The rationale for the triplet is the minimal effectiveness of BRAF inhibitors alone in colorectal cancer, “due in part to feedback through growth factor receptors such as epidermal growth factor receptor (EGFR),” Kopetz said. “The EGFR inhibitor is blunting that feedback. That feedback results in MAP kinase pathway activation. Importantly, when we look at patients who are progressing on BRAF/EGFR inhibition we’re seeing reactivation of the MAP kinase pathway through acquired alterations, including upstream. The addition is binimetinib, which is a MEK inhibitor that’s also in the MAP kinase pathway, and you get optimal pathway inhibition and blunt at least some of the mechanisms of potential acquired resistance that could occur.”

BEACON CRC is a randomized open-label 3-arm phase III study evaluating the triplet compared with irinotecan-based chemotherapy plus cetuximab and encorafenib plus cetuximab in patients with 

 V600E-mutant metastatic colorectal cancer after 1 or 2 prior lines of treatment in the metastatic setting. Enrollment was completed in 2018. BEACON SLI was conducted to evaluate safety and efficacy of the triplet prior to randomizing patients to the phase III portion.

The primary endpoint of BEACON CRC is OS associated with the triplet combination compared with the control arm.

Previously, as reported at the 2018 Gastrointestinal Cancers Symposium, the triplet combination was generally well-tolerated in the SLI. Of the 2 patients who discontinued treatment due to adverse events, 1 was considered related to treatment. The most common grade ≥3 adverse events were fatigue (n = 4), urinary tract infection (n = 3), an increase in the level of aspartate aminotransferase (n = 3), and an increase in the level of blood creatine kinase (n = 3). At that report, in the 29 patients with a BRAF V600E mutation, the estimated median PFS was 8 months and the confirmed ORR was 48%, with 3 patients achieving complete responses.

The 30 patients treated in the SLI portion of the study received encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab at the standard weekly dose of 400 mg/m

 once weekly. Of the 30 patients, 29 had a 

 V600E mutation. Median patient age was 59 years. Sixty percent had received 1 prior line of therapy and 40% received 2 prior lines. Forty-three percent received prior irinotecan. At the data cutoff of September 2, 2018, 6 patients remained on treatment.

Efficacy was evaluated in the 29 patients with 

 V600E mutations, who were on study treatment for a median of 7.9 months. The confirmed 48% ORR by local assessment consisted of 3 CRs, 11 (38%) partial responses (PRs), and 13 (45%) with stable disease (SD). The 41% ORR by central assessment included 2 CRs, 10 (34%) PRs, and 13 (45%) with SD. The median duration of response was 5.5 months by local assessment and 8.2 months by central assessment. The duration of response estimate was ≥6 months in 43% of the responders by local assessment and 73% by central assessment.

“We’re encouraged by the durability of the regimen, acknowledging that durability with doublets is on the shorter side,” said Kopetz.

When response was stratified by number of previous lines of therapy, the ORR by local assessment was 59% with 1 previous line (8 PRs and 2 CRs) and 33% (3 PRs and 1 CR) with 2 previous lines, and by central assessment, the ORR was 53% (8 PRs and 1 CR) with 1 previous line of therapy and 25% (2 PRs and 1 CR) with 2 previous lines.

The 6-month OS was 86.2% and the 12-month OS was 62.1%.

Adverse events (AEs) were similar to those previously reported with BRAF, MEK, and EGFR inhibitors. The most common grade 3/4 AEs were fatigue (n = 4), anemia, increased level of creatine kinase, asthenia, and urinary tract infection (n = 3 for each AE); dyspnea (n = 2); and gastrointestinal toxicities such as nausea, vomiting, decreased appetite (n = 2 for each). Six patients (20%) had at least 1 drug discontinued due to AEs, 1 of whom discontinued all 3 drugs due to grade-2 fatigue.

Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.

Van Cutsem, E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in in patients with 

 V600E metastatic colorectal cancer. Presented at: 2018 Gastrointestinal Symposium; January 18-20; San Francisco, CA. Abstract 627.

This article was originally published on 

Triplet Regimen Shows Durable Responses in BRAF V600E-Mutant Metastatic CRC

Preliminary findings from the SLI phase of the BEACON CRC trial show tri-drug combo has durable response in patients with BRAF V600E-mutant metastatic CRC.

Combining the BCL-2 inhibitor venetoclax (Venclexta) with endocrine therapy elicited notable activity with a tolerable safety profile in patients with estrogen receptor (ER)—positive and BCL-2–positive metastatic breast cancer.

Geoffrey J. Lindeman, MD, presented data from a phase Ib dose-escalation and expansion study, the first clinical study evaluating venetoclax in a solid tumor, at the 2018 San Antonio Breast Cancer Symposium.

Among 33 evaluable patients who received the combination of venetoclax and tamoxifen, the median progression-free survival (PFS) was 36 weeks in 15 patients treated in the dose escalation phase, 48 weeks in 18 patients treated in the expansion phase, and 36 weeks overall. Median PFS was 23 weeks in those who received doses of venetoclax <800 mg versus 51 weeks in those who received 800 mg of venetoclax, the maximum dose in the study.

The overall response rate (ORR) was 27% and the clinical benefit rate (CBR) was 67% in the dose escalation phase. No patient had a complete response (CR), and the median duration of response (DOR) was 61 weeks.

In the dose expansion phase, the ORR was 61% and the clinical benefit rate was 72%, with 1 CR. The median DOR was 39 weeks.

In the 24 patients who received 800 mg of venetoclax, the ORR was 54% and the CBR was 75%, with 1 CR (4%) and 12 partial responses (50%). The median DOR was 42 weeks. Eight patients from the 800-mg cohort remain on study treatment; the DOR reported here is until the cutoff date.

“In the primary setting, about 80% of ER-positive tumors prove to be BCL-2—positive,” said Lindeman, from the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. “What we found from this study is that about 70% of tumors remain BCL-2–positive in patients who undergo a biopsy of their metastases.”

In preclinical models of ER-positive breast cancer, venetoclax synergized with endocrine therapy.

The 3+3 dose escalation study included 15 patients who received daily venetoclax at 200 mg (n = 3), 400 mg (n = 3), 600 (n = 3), or 800 mg (n = 6) along with 20 mg of daily tamoxifen. Treatment continued until progression.

The primary endpoint was to determine the maximum tolerated dose, define dose-limiting toxicities, and identify the recommended phase II dose. In the dose-expansion phase at the recommended phase 2 dose, secondary endpoints including safety and tolerability, response at 24 weeks per RECIST v1.1, the clinical benefit rate, and PFS.

Overall, 88% of patients were strongly ER-positive and 85% were strongly BCL-2—positive. Some 79% of patients had bone metastases and 61% had visceral metastases. The mean number of prior regimens was 2 (range, 0-8), with 45% having <2 prior lines. Thirty-nine percent had prior tamoxifen exposure in the adjuvant setting, 12% in the metastatic setting only, and 36% had no prior tamoxifen exposure. Twenty-seven percent of patients had prior chemotherapy in the adjuvant setting only and 15% in the metastatic setting only; 36% did not receive prior chemotherapy.

“In our dose escalation study, we went beyond the recommended phase II dose for chronic lymphocytic leukemia, which is 400 mg/day. We got to 800 mg/day without getting to a maximum tolerated dose, so we elected to us the recommended phase 2 dose of 800 mg/day. The reason we didn’t go higher is simply that the pill burden would be too high [8 tablets a day],” said Lindeman.

Patients who achieved a metabolic response on FDG-positron emission tomography at 28 days had a significantly longer PFS than those with metabolic progression or stable metabolic disease (

“It’s hard to know with a study of this size, but we seemed to be achieving clinical responses at the 400- to 800-mg doses, but we have more experience now with the 800-mg dose,” he said. “It certainly would be predicted to give higher levels of BCL-2 in the blood, probably about double the levels of BCL-2 in the blood than the 400-mg dose.”

No patient had to discontinue on the basis of toxicity. The main side effects with venetoclax were on-target effects, including grade 1-3 lymphopenia, “which didn’t cause any other adverse events of infections to our knowledge,” Lindeman said.

Lymphopenia occurred in 100% at venetoclax doses <800 mg and in 83% at the 800-mg dose. Neutropenia occurred in 56% at doses <800 mg and in 79% in those dosed at 800 mg. Thirty-eight percent had an infection at the 800-mg dose compared with none at lower doses.

“The other side effect we see is low-grade nausea, which occurs a couple of hours after taking the tablets and is often ameliorated by giving antiemetic tablets like metoclopramide,” he said. “Otherwise, we saw very few side effects with venetoclax in this small phase Ib study.”

Sixty-seven percent of patients experienced nausea at the <800-mg dose.

Lindeman said that investigators have already initiated a phase II trial called VERONICA. BCL-2-positive patients who have progressed on a CDK4/6 inhibitor will be randomly assigned to fulvestrant with or without 800 mg of venetoclax.

Lindeman GJ, Lok SW, Whittle JR, et al. A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2—positive metastatic breast cancer (MBC). Presented at: Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract PD1-06.

Venetoclax Has Impressive Activity in ER+ and BCL-2+ Breast Cancer

Combining the BCL-2 inhibitor venetoclax (Venclexta) with endocrine therapy elicited notable activity with a tolerable safety profile in patients with estrogen receptor (ER)–positive and BCL-2–positive metastatic breast cancer.

CT-P6, a proposed biosimilar to trastuzumab (Herceptin), exhibited long-term disease-free survival (DFS) and overall survival (OS) similar to the reference product in the treatment of patients with HER2-positive early 

. Two-year results from a phase III comparison confirmed the similar efficacy and safety that was apparent at 1 year.

CT-P6, a proposed biosimilar to trastuzumab, exhibited long-term disease-free survival (DFS) and overall survival (OS) similar to the reference product in the treatment of patients with HER2-positive early breast cancer. 

Wayne Kuznar