The OBR Blog

May 31, 2020 - 08:05 pm Posted in ASCO and ASH Posted in ASCO Conference Coverage Posted in Breast Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) Posted in Melanoma (includes BCC) Posted in Multiple Myeloma comments0 Comments

Sunday’s live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting featured late-breaking data from a phase 3 trial evaluating early local therapy in metastatic breast cancer and the results of the phase 3 ENDURANCE trial.

Other important studies from the meeting were the ALPHA trial, which is evaluating an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy, and the C-144-01 trial, which is evaluating an autologous tumor infiltrating lymphocyte (TIL) therapy.

Early local therapy offers no survival benefit in patients with de novo metastatic breast cancer and an intact primary tumor, according to the results of a phase 3 trial by the ECOG-ACRIN Research Group (Abstract LBA2).

The trial included 256 patients who received optimal systemic therapy before being randomly assigned to either continue optimal systemic therapy (n=131) or receive optimal systemic therapy with locoregional therapy (n=125).

The 3-year overall survival (OS) rate was not different for the locoregional therapy arm compared with the optimal systemic therapy alone arm (68.4% vs 67.9%; P=0.63) and neither was the risk of death (HR=1.09; 90% CI, 0.80 – 1.49).

Although the locoregional therapy arm had a reduced risk of locoregional recurrences/progression compared with the optimal systemic therapy alone arm (HR=0.37; 95% CI, 0.19 – 0.73), no improvements were seen for health-related quality of life (HRQOL). At one timepoint (18 months), HRQOL was significantly worse for the locoregional therapy arm (P=0.001).

“For de novo stage metastatic breast cancer, existing data supports that locoregional therapy does not improve survival and should not be routinely applied in this population,” said study discussant Julia White, MD, professor of radiation oncology at The Ohio State University.

Carfilzomib and Bortezomib Tie for First

The replacement of carfilzomib for bortezomib in a regimen of bortezomib, lenalidomide, and dexamethasone (VRd) did not improve outcomes for patients with newly diagnosed multiple myeloma, results showed in the second interim analysis of the phase 3 ENDURANCE trial (Abstract LBA3).

Patients who received carfilzomib, lenalidomide, and dexamethasone (KRd; n=545) had a similar progression-free survival (PFS; HR=1.04; 95% CI, 0.8 – 1.3; P=0.74) and OS (HR=0.98; 95% CI, 0.71 – 1.36; P=0.92) to those who received VRd (n=542). A higher proportion of particularly good partial responses was seen with KRd compared with VRd (55.5% vs 49.9%).

KRd had a significantly higher rate of cardiac, pulmonary, and renal treatment-related adverse events (16.1% vs 4.8%; P<0.001), while VRd had a significantly higher rate of peripheral neuropathy (53.4% vs 24.4%; P<0.001). No difference in frequency of secondary primary cancers was seen.

Study discussant Jesus Berdeja, MD, director of myeloma research at Sarah Cannon Research Institute, pointed out that KRd costs nearly $16,000 more per cycle than VRd, which totals to a nearly $100,000-difference for 12 cycles.

“In newly diagnosed multiple myeloma without high-risk features, VRd and KRd appear to be equivalent options for frontline treatment,” Dr Berdeja said. “Comorbidities and toxicity profiles should guide the choice between the two regimens in any individual patient.”

ALPHA Trial Debuts Off-the-Shelf CAR T

An off-the-self allogeneic CAR T-cell therapy known as ALLO-501 appeared safe and showed clinical activity in a small group of patients with relapsed or refractory large B-cell or follicular lymphoma, according to data from the single-arm phase 1 ALPHA trial (Abstract 8002).

“Allogeneic CAR T-cell therapy may provide the benefits of autologous CAR T-cell therapy, while also addressing its challenges,” said study presenter Sattva Neelapu, MD, MD Anderson Cancer Center. “It has the potential to treat all eligible patients, the convenience of repeat dosing, and simplifies the logistics of manufacturing.”

Patients received CD19-targeted ALLO-501 at one of three dose levels and, during lymphodepleting chemotherapy, an investigational monoclonal antibody called ALLO-647, which targets CD52. Patients were heavily pretreated (median of 4 prior therapies), and 4 patients previously received autologous CAR T-cell therapy.

About one-third of patients (7 of 22) had cytokine release syndrome, which included only one grade 3 event and no grade 4. Half of patients developed infection, most of which was grade 1 (23%) or 2 (18%). There were no reports of graft-versus-host disease.

At a median follow-up of 3.8 months, 12 of 19 patients (63%) available for efficacy analysis achieved a response, which included 7 complete responses (37%). Nine patients who achieved a response continue to have a response.

Dr. Neelapu said these results suggest that the safety and the short-term efficacy, in terms of the response rates, for this product is “comparable” to autologous CAR-T products that are currently in clinic. “Further follow-up is necessary to determine the durability of those responses.”

C-144-01 Trial Shows Potential of TILs

Autologous TIL therapy lifileucel appeared safe and to have clinical activity in patients with unresectable metastatic melanoma, according to the results of cohort 2 from the phase 2 C-144-01 trial (Abstract 10006).

Lifileucel is an autologous adoptive cell transfer therapy that involves surgically resecting a patient’s tumor and sending it to the manufacturing facility. Tumor infiltrating lymphocytes (TILs) are then obtained from the tumor, expanded, shipped back to clinical sites, and infused into the patient. Patients in cohort 2 (n=66) received lifileucel that was cryopreserved before shipment. Patients also received up to 6 doses of interleukin-2 after infusion to promote expansion of the TILs.

Most patients (97.0%) had grade 3 or 4 treatment-emergent adverse events, with thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%) being the most common. The number of adverse events decreased over time.

Overall, 24 (36.4%) patients achieved a response, which included 2 complete and 22 partial responses. The disease control rate was 80.3%. At a median follow-up of 18.7 months, the median duration of response had not yet been reached (range, 2.2 – 26.9+ months). Responses were seen across subgroups, which include age, PD-L1 status, and BRAF mutation status.

“Notable, observed responses tended to deepen over time,” said study presenter Amod Sarnaik, MD, Moffitt Cancer Center. “These data therefore demonstrate potential efficacy and durability of response in a patient population with severely limited treatment options.”

By Christina Bennett, MS

 

May 30, 2020 - 09:05 pm Posted in ASCO and ASH Posted in ASCO Conference Coverage Posted in Breast Posted in Liver (includes HCC, Billiary Tract) comments0 Comments

The live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting kicked off this morning with highlights sessions that captured some of the most important studies.

The gastrointestinal cancer session featured four studies, one of which was a phase 2/3 trial that compared donafenib to sorafenib in liver cancer. HER2CLIMB and MINDACT were both discussed during the breast cancer session. Although not discussed this morning, the results of PHERGAIN dropped at this meeting and offer a de-escalation strategy for patients with early breast cancer.

Another Blow to Sorafenib

Patients with unresectable or metastatic hepatocellular carcinoma who received donafenib in the first-line setting lived a median of nearly two months longer than patients who received standard of care sorafenib (12.1 months vs 10.3 months), results showed in the open-label, randomized phase 2/3 trial (Abstract 4506).

Patients in the donafenib arm (n=334) also had a 17% reduced risk of death compared with the sorafenib arm (n=334; HR=0.831; 95% CI, 0.699 – 0.988; P=0.0363). However, no difference was seen between the donafenib arm and sorafenib arm for progression-free survival (PFS; 3.7 vs 3.6 months; P=0.2824), objective response rate (4.6% vs 2.7%; P=0.2448), and disease control rate (30.8% vs 28.7%; P=0.5532).

Donafenib appeared to have a better safety profile, with a significantly lower rate of drug-related adverse events that led to treatment interruption compared with sorafenib (25.2% vs 36.1%; P=0.0025). The donafenib arm also had a significantly lower rate of drug-related adverse events of grade 3 or higher (37.5% vs 49.7%; P=0.0018).

Marcus Noel, MD, associate professor of medicine, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, cautioned that this study was conducted in China and is not an international study.

“Not sure if this is going to be able to extrapolate across the globe, but certainly donafenib has a place in first-line therapy, further pushing sorafenib to the side,” he said.

Tucatinib Shows Promise for Brain Mets

Tucatinib in combination with trastuzumab and capecitabine extended overall survival (OS) and delayed disease progression in the central nervous system (CNS) for patients with HER2-positive metastatic breast cancer and brain metastases, results showed from an exploratory efficacy analysis of the phase 2 HER2CLIMB trial (Abstract 1005).

Trial participants were randomly assigned to receive tucatinib in combination with trastuzumab and capecitabine (n=410) or placebo in combination with trastuzumab and capecitabine (n=202). The exploratory analysis included only patients with brain metastases at baseline, of which 291 of 612 (48%) randomized to treatment had.

Patients with brain metastases in the tucatinib arm had a 68% reduced risk of disease progression in the CNS compared with the placebo arm (HR=0.32; 95% CI, 0.22 – 0.48; P<0.0001) and a nearly 6-month gain in median CNS PFS (9.9 vs 4.2 months).

Patients in the tucatinib arm also had a 42% reduced risk of death compared with the placebo arm (HR=0.58; 95% CI, 0.40 – 0.85; P=0.005), and an approximately 6-months gain in overall survival (OS; 18.1 vs 12.0 months). The intracranial response rate more than doubled with tucatinib compared with placebo (47% vs 20%; P=0.03).

“HER2CLIMB serves as a wonderful story for the liberalization of clinical trial entry criteria and inclusion of patients that we need in clinical trials and who need novel therapeutics as well,” said Erika Hamilton, MD, Sarah Cannon.

MINDACT Confirms Clinical Utility of MammaPrint

A long-term analysis of the phase 3 MINDACT trial confirmed that the 70-gene signature MammaPrint assay can identify which breast cancer patients with a high clinical-pathological risk do not need adjuvant chemotherapy (Abstract 506).

Among the intention to treat population with a median follow-up of 8.7 years, patients with high clinical risk but low genomic risk who received adjuvant chemotherapy (n=749) had a small gain in distant metastasis-free survival (DMFS) compared with patients who did not receive chemotherapy (n=748; 92.0%; 95% CI, 89.6 – 93.8% vs 89.4%; 95% CI, 86.8 – 91.5).

A subgroup analysis among hormone-receptor positive and HER2-negative patients revealed no difference in DMFS between treatment groups for patients over the age of 50, yet a 5% difference for patients 50 years or younger, favoring treatment with chemotherapy (93.6%; 95% CI, 89.3% – 96.3% vs 88.6%; 95% CI, 83.5 – 92.3%).

“MINDACT showed us that patients with clinical high, genomic low disease continue to do well without chemotherapy at 8 years of follow-up,” said Angela de Michele, MD, University of Pennsylvania. She cautioned that the DMFS gain seen with chemotherapy for premenopausal patients “may be due to a lack of ovarian function suppressant in the non-chemotherapy arm.”

PHERGAIN Showcases De-escalation Strategy

A PET/CT scan with fluorodeoxyglucose (FDG) tracer helped identify which patients with HER2-positive early breast cancer were most likely to benefit from trastuzumab and pertuzumab with endocrine therapy, according to the results of the PHERGAIN trial (Abstract 503).

Patients with HER2-positive disease were randomized to receive either trastuzumab and pertuzumab with chemotherapy (n=71) or trastuzumab and pertuzumab with endocrine therapy (n=285).

A PET/CT scan was used to guide treatment for patients in the chemotherapy-free arm by having patients undergo imaging after 6 weeks of treatment. If the scan showed a response, patients continued on the chemotherapy-free regimen. If not, patients switched to trastuzumab and pertuzumab with chemotherapy. Patients in the chemotherapy-containing arm also underwent imaging but the results were not used to guide treatment.

For the chemotherapy-free arm, patients who had a PET response achieved a higher pathologic complete response rate compared with patients who did not have a PET response (37.9% vs 25.9% P=0.069).

Study presenter Javier Cortes, MD, PhD, IOB Institute of Oncology, Hospital Quirónsalud, Medica Scientia Innovation Research, and Vall d’Hebron University of Oncology, said the chemotherapy-free strategy did not “jeopardize” breast conserving surgery and was also associated with a “more favorable” toxicity profile.

By Christina Bennett, MS

May 29, 2020 - 01:05 am Posted in ASCO and ASH Posted in ASCO Conference Coverage comments0 Comments

Ahead of this weekend’s live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, late-breaking data dropped for three potentially practice-changing studies that will be presented during Sunday’s Plenary Session: JAVELIN Bladder 100, KEYNOTE-177, and ADAURA.

JAVELIN Bladder 100

The addition of avelumab to best supportive care (BSC) in the maintenance setting appeared to benefit patients with unresectable advanced urothelial carcinoma who had received first-line platinum-based chemotherapy, according to an interim analysis of the phase 3 JAVELIN Bladder 100 trial (Abstract LBA1).

At median follow-up of approximately 19 months, overall survival (OS) was significantly longer for patients who received avelumab plus BSC (n=350) compared with BSC alone (n=350; HR=0.69; 95% CI, 0.56-0.86; P=0.0005). This benefit was seen across all subgroups. Patients with PD-L1–positive tumors also had significantly prolonged OS with avelumab plus BSC compared with BSC alone (HR=0.56; 95% CI, 0.40-0.79; P=0.0003).

Progression-free survival (PFS) was significantly longer for patients who received avelumab plus BSC compared with BSC alone (HR=0.62; 95% CI, 0.52-0.75; P<0.001), including those with PD-L1–positive tumors (HR=0.56; 95% CI, 0.43-0.73).

Patients who received avelumab plus BSC had a higher frequency of any grade (98.0% vs 77.7%) or grade 3 or higher (47.4% vs 25.2%) adverse events (AEs) compared with BSC alone. Common grade 3 or higher AEs for both arms were urinary tract infection, anemia, hematuria, fatigue, and back pain, all of which occurred at similar frequencies between arms.

Study presenter Thomas Powles, MD, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hospital, described the safety profile of avelumab as “in line” with other immune checkpoint inhibitors in this setting.

“Overall, avelumab first-line maintenance therapy in patients whose disease has not progressed with platinum-based induction chemotherapy is a new first-line standard of care for advanced urothelial cancer,” said Dr. Powles.

KEYNOTE-177

Pembrolizumab showed superior PFS compared with chemotherapy in patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer, meeting the primary endpoint of the phase 3 KEYNOTE-177 trial (Abstract LBA4).

At median follow-up of approximately 28 months, median PFS was more than 8 months longer for the pembrolizumab arm (n=153) compared with the chemotherapy arm (n=154; 16.5 vs 8.2 months), with a 40% reduction in risk of disease progression (HR=0.60; 95% CI, 0.45-0.80; P=0.0002).

At one year, PFS was higher for the pembrolizumab arm compared with the chemotherapy arm (55.3% vs 48.3%), which remained at 2 years (37.3% vs 18.6%). The overall response rate was also higher for the pembrolizumab arm compared with the chemotherapy arm (43.8% vs 33.1%), as was the complete response rate (11.1% vs 3.9%).

Pembrolizumab appeared to have a better safety profile, eliciting a lower frequency of grade 3 or higher AEs than chemotherapy (22% vs 66%). Also, no treatment-related deaths were reported for the pembrolizumab arm, while one was reported for the chemotherapy arm.

Study presenter Thierry Andre, MD, Sorbonne University and Saint-Antoine Hospital, described the PFS improvement seen with pembrolizumab as “clinically meaningful” and said pembrolizumab should be the “new standard of care” for this patient population.

ADAURA

Adjuvant osimertinib showed significantly improved disease-free survival (DFS) compared with placebo for patients with EGFR-mutation–positive NSCLC in the phase 3 ADAURA trial (Abstract LBA5).

The trial included 682 patients with stage IB to IIIA EGFR-mutation–positive NSCLC who were randomized to receive adjuvant osimertinib (n=339) or placebo (n=343) after complete tumor resection. Patients were given the option of having adjuvant chemotherapy before the assigned treatment.

The trial met its primary endpoint, showing an 83% reduction in risk of disease for patients with stage II to IIIA disease who received adjuvant osimertinib compared with placebo (DFS HR=0.17; 95% CI, 0.12 – 0.23; P<0.0001). The osimertinib arm had a 2-year DFS rate of 90% and placebo 44%.

When stage IB patients were included in the analysis, the osimertinib arm had a 79% reduction in risk of disease recurrence (DFS HR=0.21; 95% CI, 0.16 – 0.28; P<0.0001), with a 2-year DFS rate of 89% for osimertinib and 53% for placebo.

Common AEs seen with osimertinib were diarrhea (46%), paronychia (25%), dry skin (23%), and pruritis (19%), all of which were higher than those receiving placebo. No reported AEs with osimertinib lead to death. Overall, 3% of patients who received osimertinib developed interstitial lung disease and 7% QTc prolongation.

“Adjuvant osimertinib is the first targeted agent in a global randomized trial to show statistically significant and clinically meaningful improvement disease-free survival in patients with stage IB to IIIA EGFR-mutation–positive non-small cell lung cancer,” said study presenter, Roy Herbst, MD, PhD, Yale School of Medicine and Yale Cancer Center.

By Christina Bennett, MS

 

May 29, 2020 - 01:05 am comments0 Comments

Several late-breaking abstracts dropped ahead of this weekend’s live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting. The studies cover new data from two cancer registries (CCC19 and TERAVOLT) assessing the impact of COVID-19 on patients with cancer, and results from the TROPHIMMUN trial and INFORM registry.

CCC19

Patients with cancer and COVID-19 had a heightened risk of dying if they had active disease, according to the first analysis of an ongoing COVID-19 and Cancer Consortium (CCC19) registry (Abstract LBA110).

Among 928 patients included in the analysis, 121 (13%) died at a median follow-up of 21 days. A multivariable logistic regression model that was partially adjusted revealed several factors associated with increased risk of death: older age, male sex, former smoking, high number of comorbidities , ECOG performance status great than 2, and active cancer.

For those with active cancer, having a stable or responsive disease was associated with a nearly two-fold increased risk (partially adjusted odds ratio [pAOR]=1.93; 95% CI, 1.06-3.5) and disease progression a nearly four-fold increased risk (pAOR=3.79; 95% CI, 1.78-8.08).

Receipt of azithromycin and hydroxychloroquine together was also associated with an increased risk of death. However, study presenter Jeremy Warner, MD, associate professor of medicine and biomedical informatics at Vanderbilt University Medical Center, cautioned that this finding is of “uncertain validity” due to a “high risk of residual confounding.”

“For example,” he said, “patients receiving this combination were more likely to have severe disease or more likely to be hospitalized.”

TERAVOLT

Prior receipt of chemotherapy, but not immunotherapy or tyrosine kinase inhibitors, was associated with increased risk of death for patients with thoracic malignancies and COVID-19, according to an updated analysis of the ongoing Thoracic cancERs international coVid 19 cOLlaboraTion (TERAVOLT) registry (Abstract LBA111).

Among 400 patients included in the analysis, 141 (35%) died at a median follow-up of 33 days. Most deaths (79.4%) were attributed to only COVID-19, while 10.6% were attributed to cancer. Most patients were hospitalized (78.3%).

A multivariate analysis revealed that age, ECOG performance status, use of steroids of greater than 10 mg per day, and prior receipt of chemotherapy were associated with increased risk of death. None of the therapies given to treat COVID-19 were significantly associated with outcomes.

TROPHIMMUN

Avelumab appeared to benefit patients with gestational trophoblastic tumors (GTT) resistant to monochemotherapy, according to data from cohort A of the TROPHIMMUN phase 2 trial (abstract LBA6008).

GTT are characterized by high levels of human chorionic gonadotropin (hCG), and among the 15 patients from cohort A who received avelumab after developing resistance to monochemotherapy, 7 achieved normal levels of hCG during treatment and one was achieved after.

No patients had disease relapse, which study presenter Benoit You, MD, PhD, Institut de Cancérologie des Hospices Civils de Lyon, interpreted as meaning these patients were “potentially cured.”

One woman who achieved normal levels of hCG went on to have a normal pregnancy and healthy baby, which is the first report of a patient achieving a normal pregnancy after treatment with immunotherapy.

No patients required dose reductions or delays, and common adverse events were fatigue (33%), nausea and vomiting (33%), infusion-related reactions (27%), thyroid disorder (20%), dry eyes (20%), and diarrhea (20%).

A phase 1/2 trial called TROPHAMET is ongoing to evaluate avelumab with methotrexate as a first-line treatment for patients with GTT.

INFORM

A 7-step treatment algorithm successfully identified molecular targets in children with relapsed cancers and matched them to targeted therapies; a subset of these patients even had a clinical benefit (abstract LBA10503).

Part of the INFORM registry, 526 children were evaluated with the treatment algorithm and 149 were matched to targeted drugs, of whom 20 had a very-high priority molecular target. Extremely high priority targets were primarily ALK, BRAF, and NRAS mutations and MET and NTRK-fusions.

The algorithm also identified 40 children with potential cancer predisposition syndrome, 17 of which were unaware of having the syndrome.

The subset of children with a very-high priority target had a significantly longer progression-free survival compared with the rest of the children (204.5 days vs 114 days; P=0.0093).

A set of biomarker-driven pediatric phase 1/2 trials, known as INFORM2, are underway.

By Christina Bennett, MS

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