November 2018 Edition Vol.11, Issue 11

Trials Presented at ESMO 2018 Considered Practice Changing

By Ted Bosworth

An immunotherapy-based regimen in triple-negative breast cancer, a maintenance therapy in ovarian cancer, and a new strategy for HR+/HER2- breast cancer no longer responding to hormone therapy were among six practice changing treatment strategies presented at the European Society of Medical Oncology (ESMO) 2018 Congress.

Of the others, two involved improved outcomes with immunotherapy-based regimens in renal cell and head and neck carcinoma, while the third found radiotherapy at the time of diagnosis to improve survival in a subset of metastatic prostate cancer patients.

Traditionally, new cancer regimens are considered practice changing when they show an overall survival (OS) benefit over a previous standard of care treatment. In the practice changing cases presented, some met this criterion while others showed an OS advantage only in a subset of patients. Others were considered practice changing on the basis of improved progression-free survival (PFS) in poor prognosis cancer for which treatment options have been inadequate and limited.

IMpassion130 Trial: New Standard in Triple-Negative Breast Cancer

In the phase 3 IMpassion130 study, conducted in patients with locally advanced or metastatic triple-negative breast cancer, the OS advantage from adding an anti-PD-L1 checkpoint inhibitor to standard therapy fell just short of statistical significance relative to standard therapy alone. However, patients positive for the PD-L1 biomarker had a large OS gain. The new therapy was considered a breakthrough for an aggressive form of breast cancer with limited treatment options.

“The IMpassion130 data will probably change the treatment landscape for our metastatic triple negative breast cancer patients,” said Marleen Kok, MD, PhD, a breast cancer specialist at the Netherlands Cancer Institute, Amsterdam. Not an IMpassion130 investigator, Dr. Kok was invited to provide independent expert comment on the significance of the findings. She called the gain in survival among the subgroup of patients positive for PD-L1 “impressive.”

Results from this trial are published in Schmid P et al. N Engl J Med 2018; October 20 [epub ahead of print]. Triple-negative patients (n=451) were randomized to receive nanoparticle albumin-bound (nab)-paclitaxel with placebo or in combination with the immunotherapy atezolizumab, which targets the PD-L1 checkpoint. At baseline, tumor tissue was evaluated for PD-L1 expression. PFS and OS were co-primary endpoints.

At 12.9 months of followup, median PFS increased from 5.5 months in the standard chemotherapy arm to 7.2 months in the immunotherapy-containing arm, producing a 20% reduction in the hazard ratio (HR) for progression or death (P=0.002). The nearly three-month OS improvement (21.3 vs 17.6 months) fell just short of statistical significance (HR 0.84; P=0.08), but median OS climbed from 15.5 months in the standard arm to 25 months in the atezolizumab arm (HR 0.62; p value significant but pending) among patients with ≥1% of immune cells expressing PD-L1.

“Atezolizumab combined with nab-paclitaxel is the first targeted treatment to improve survival in metastatic triple-negative breast cancer,” according to the principle investigator Peter Schmid, MD, PhD, Clinical Director, St. Bartholomew’s Breast Cancer Centre, London, UK.

Relative to nab-paclitaxel alone, the most notable adverse event in the atezolizumab arm was a greater incidence of hypothyroidism (17.7% vs 4.3%). More studies are needed to evaluate the role of PD-L1 as a biomarker, according to Dr. Schmid, but he called the combination of atezolizumab and nab-paclitaxel an important new treatment option for metastatic triple-negative disease.

SOLO-1 Trial: Maintenance Olaparib Dramatically Extends PFS in Ovarian Cancer

In BRCA-positive ovarian cancer patients, two years of maintenance olaparib produced a large improvement in median PFS relative to placebo. Perhaps more importantly, 50% of women receiving maintenance therapy were disease-free after four years of followup. This extended disease-free period—achieved in only 11% of placebo patients—raises hope of very long-term responses for some patients.

“These are outstanding results,” asserted Isabelle Ray-Coquard, MD, an ovarian disease specialist from the Université Claude Bernard-Lyon Est, Lyon, France. “The findings promise to change practice,” she added.

Published results are in Moore K et al. N Engl J Med 2018; October 21 [epub ahead of print]. Patients with advanced high-grade serous or endometrioid BRCA1/2 mutation (n=391) were randomized in a 2:1 ratio to two years of maintenance therapy with 300 mg olaparib twice daily or placebo after cytoreductive surgery and chemotherapy. Olaparib, a PARP inhibitor, is already approved for maintenance treatment in platinum-sensitive ovarian cancer after a prior relapse. PFS was the primary endpoint.

At 41 months of median followup, rates of freedom from disease progression and death at three years were 60% for those randomized to olaparib versus 27% for those receiving placebo (HR 0.30; P<0.001). The median time to need for a subsequent therapy or death was 51.8 months in the olaparib group versus 15.1 months in the placebo group (Fig. 1).

“It is too early to say whether we have impacted the fraction of women who could be cured with their front-line therapy with the addition of olaparib maintenance,” said the principle investigator Kathleen Moore, MD, associate professor at the Stephenson Cancer Center, University of Oklahoma, Oklahoma City. However, the “outstanding improvement was maintained even after olaparib was stopped.”

Olaparib-associated toxicities were largely hematological and did not adversely impact quality of life. A potential OS benefit is being monitored in ongoing followup.

PALOMA-3 Trial Confirms Survival Benefit for Palbociclib in Breast Cancer

In patients with hormone-receptor positive (HR+), HER2-negative advanced breast cancer who had disease progression after a previous endocrine therapy, adding the CDK4/6 inhibitor palbociclib to fulvestrant increased median OS by 6.9 months relative to fulvestrant plus placebo, according to results from the PALOMA-3 trial. While a PFS benefit was previously reported (Cristofanilli M et al. Lancet Oncology 2016;17:425-439), the OS benefit, which was even greater in patients with sensitivity to prior endocrine therapy, was said to validate this approach as a possible new standard.

“Collecting mature OS data with longer followup is crucial to have a clearer understanding of the benefit of these expensive agents,” said Carmen Criscitiello, MD, European Institute of Oncology, Milan, Italy. However, she added that the data suggest “this treatment should become widely available for women with advanced HR+/HER2- disease.”

Results are published in Turner NC et al. N Engl J Med 2018; October 20 [epub ahead of print]. Patients with HR+/HER2- advanced breast cancer and progression or relapse during previous endocrine therapy (n=521) were treated with fulvestrant and randomized to receive palbociclib or placebo. The median OS was 34.9 months in palbociclib arm versus 28 months in the placebo arm (P=0.043). In the 410 patients who had demonstrated sensitivity to previous endocrine therapy, the addition of palbociclib to fulvestrant raised the median OS from 29.7 to 39.7 months (HR 0.72; P value not reported).

Grade 3 or higher neutropenia occurred in 70% of patients receiving both palbociclib and fulvestrant, but febrile neutropenia was reported in only 1%. Non-hematologic adverse events of grade 3 or higher were uncommon whether or not palbociclib was combined with fulvestrant.

The OS benefit provides “additional confidence to clinicians and patients as to the benefits of this combination as an appropriate and effective treatment approach,” reported the senior author, Massimo Cristofanilli, MD, Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago.

JAVELIN Renal 101: First-Line Immunotherapy Plus Axitinib Improves PFS in RCC

In patients with previously untreated advanced renal cell carcinoma (RCC) whose tumors were positive for the PD-L1 checkpoint, a combination of the checkpoint inhibitor avelumab and the tyrosine kinase inhibitor (TKI) axitinib increased the median PFS from 8.4 months to 13.8 months when compared with the TKI sunitinib (HR 0.69; P=0.0001). The relative advantage was greater (13.8 vs 7.2 months) among those with measureable PD-L1 expression on immune cells.

“For a malignancy with a very poor prognosis, these response rates are eye-catching,” said Thomas Powles, MD, Director of Barts Cancer Institute, London, and an expert on kidney cancer. Dr. Powles said the data support immunotherapy as an important new option, although he cautioned that a final assessment awaits OS data, which are being evaluated but are not yet mature.

In this trial, 886 patients with advanced clear-cell RCC were randomized to 10 mg/kg of avelumab administered every two weeks plus 5 mg of axitinib twice daily or to 50 mg of sunitinib taken once daily. PFS was determined with RECIST criteria on independent review.

“The combination of immunotherapy and axitinib was favored for PFS and objective response irrespective of PD-L1 expression or prognostic groups determined with MSKCC/MDC prognostic criteria,” said lead author, Robert Motzer, MD, Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Institute, New York.

Grade 3 or higher adverse events were observed in 71.2% of those treated with the immunotherapy regimen; 71.5% in those receiving sunitinib. Discontinuations due to side effects occurred in 22.8% and 13.4%, respectively. Deaths attributed to treatment were slightly higher in the immunotherapy group (0.7% vs 0.2%).

Characterizing the study “as the first positive phase 3 trial combining a checkpoint inhibitor with a TKI in first-line treatment of advanced RCC,” Dr. Motzer believes these data “support avelumab plus axitinib as a potential new first-line standard-of-care” for all patients with advanced RCC not just those with PD-L1-positive tumors.

KEYNOTE 048: Survival Advantage Supports Immunotherapy in Metastatic Head and Neck Cancer

When compared with a standard platinum-based chemotherapy regimen, the addition of the checkpoint inhibitor pembrolizumab improves OS in metastatic or recurrent head and neck cancer positive for PD-L1, according to the phase 3 KEYNOTE 048 trial. PD-L1 positivity was defined by the Combined Positive Score (CPS), which is calculated by dividing the number of cells positive for PD-L1 staining by the total number of cells. In this study, PD-L1 CPS cutoffs of ≥20 and CPS ≥1 were evaluated.

“This is the first study to show superior overall survival over platinum-based chemotherapy plus cetuximab, a decade-old standard of care,” said Tanguy Seiwert, MD, Program Director, Head and Neck Cancer, University of Chicago, Illinois. Not an investigator for KEYNOTE 048, Dr. Tanguy said it is important to recognize that the advantage of pembrolizumab was confined to those with PD-L1 positive tumors. However, he said that PD-L1 can now be considered an important disease marker “that should be routinely measured” in advanced disease to guide therapy.

There were two comparisons in KEYNOTE 048. In both, head and neck cancer patients not previously treated for recurrent or metastatic disease were enrolled. In one study (n=301), pembrolizumab alone was compared with a standard platinum-based regimen (cisplatin or carboplatin with 5-FU) plus cetuximab. In the other (n=281), pembrolizumab plus this standard platinum-based regimen was compared with standard treatment alone.

In the first comparison, OS was significantly greater in the group receiving pembrolizumab (14.9 vs 10.7 months; HR 0.61; P=0.0007) among those with CPS ≥20 (Fig. 2).

In the group with the lower CPS ≥1 cut-off, OS was also significantly greater although the difference was smaller (12.3 vs 10.3 months; HR 0.71; P=0.0086). Although there was no between-group difference in PFS, the median response duration was substantially greater (20.9 vs 4.5 months) in the pembrolizumab arm.

In the second comparison, OS was also greater in those receiving pembrolizumab irrespective of PD-L1 status (13.0 vs 10.7 months; HR 0.77; P=0.0034). The OS advantage of adding pembrolizumab to platinum-based chemotherapy was achieved despite similar objective response and PFS rates.

Adding pembrolizumab to standard therapy produced similar rates and types of toxicities relative to standard therapy alone, according to the presenting author, Barbara Burtness, MD, professor of medicine, Yale University School of Medicine, New Haven, Connecticut.

It appears that the decision to use pembrolizumab alone or add it to standard chemotherapy “may depend on PD-L1 expression,” according to Dr. Burtness, who is “currently conducting analyses to answer this question,” but she concluded from these data that head and neck cancer patients with recurrent or metastatic tumors positive for PD-L1 “live longer when they receive pembrolizumab.”

 

STAMPEDE Trial: Radiotherapy at Time of Diagnosis Improves Survival in Selected Metastatic Prostate Cancer Patients

In men with prostate cancer and a low metastatic burden, radiotherapy at the time of diagnosis improves OS, according to the phase 3 STAMPEDE trial. Designed to determine whether radiotherapy can improve local control of metastatic disease, the study showed that it could, but only in patients with a low metastatic burden.

“For men with newly diagnosed oligometastatic prostate cancer, it is quite likely that these data are practice changing,” said Karim Fizazi, MD, Gustave Roussy Institute, Villejuif, France. Dr. Fizazi questioned whether upfront radiotherapy might reduce symptoms in those with a higher burden of disease even without an OS benefit, but this has yet to be determined.

In STAMPEDE, 2061 men with newly diagnosed metastatic prostate cancer were randomized to standard of care or standard of care plus a course of radiotherapy. Overall, the 8% overall improvement in OS (HR 0.92) for radiotherapy relative to no radiotherapy did not reach significance, but relative to no change in OS for the high metastatic burden group (HR 1.07), there was a 32% reduction in death for the 819 patients with a low burden (HR 0.68; 95% CI 0.52, 0.90), according to the presenting author, Chris Parker, MD, a clinical oncologist at Royal Marsden NHS Foundation Trust, Sutton, UK.

“Prostate radiotherapy should now be a standard option along with drug treatment for newly diagnosed oligometastatic prostate cancer,” Dr. Parker reported, calling radiotherapy, which was well tolerated, “simple, widely available, and relatively cheap.”

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