The OBR Blog

February 06, 2018 - 08:02 pm comments0 Comments

This week is turning out to be a busy and exciting week in readouts from Phase 3 clinical trials, including results from the CheckMate 227 trial in first-line advanced non-small cell lung cancer; the IMmotion 151 trial in unresectable locally advanced or metastatic renal cell carcinoma; and the COLUMBUS trial in melanoma.

Progression-free survival in NSCLC
First up, Bristol-Myers Squibb (BMS) announced yesterday significant results for its ongoing Phase 3 CheckMate 227 study. The study met its co-primary endpoint of progression-free survival (PFS) with an Opdivo (nivolumab; BMS) plus Yervoy (ipilimumab; BMS) combination arm versus chemotherapy in first-line advanced non-small cell lung cancer (NSCLC) patients whose tumors have high (≥10 mutations/megabase, mut/mb) tumor mutation burden (TMB), regardless of PD-L1 expression.

“For the first time, this Phase 3 study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” said Matthew D. Hellmann, MD, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center.

Using Foundation Medicine’s FoundationOne CDx validated assay, CheckMate 227 is an open-label Phase 3 trial that randomized more than 2,500 non-squamous and squamous histologies to an Opdivo-based treatment arm or to platinum-doublet chemotherapy. The study is being carried out in three parts, and yesterday’s announcement is the result of Part 1.

Critics are pointing out the modification of only assessing patients with tumors with high TMB (≥10 mutations/megabase) — BMS enacted a change on the trial design that could have affected whether PFS was significant. Other critics point out that the threshold BMS used for high TMB is far lower than the established FoundationOne threshold of >20 mut/mb found in only about 13% of patients.

Hellmann said, “TMB has emerged as an important biomarker for the activity of immunotherapy.” Hellmann is correct in that statement, but TMB was not a prospectively identified biomarker, and its threshold here does not align with a consensus of TMB threshold. Subset analyses and the overall survival (OS) readout should provide a much clearer picture on the best candidates for and the efficacy of the Opdivo plus Yervoy combination in advanced NSCLC.

Lung cancer expert Jack West, MD, is an editor on the OBR editorial board. He provided OBR with a full analysis of these results. To see his comments please click here.

Results from IMmotion 151 in renal cell carcinoma
Continuing in immunotherapy, Roche announced results from its Phase 3 trial, IMmotion 151, of Tecentriq (atezolizumab; Genentech) plus Avastin (bevacizumab; Genentech) versus standard-of-care Sutent (sunitinib; Pfizer) in patients with unresectable locally advanced or metastatic renal cell carcinoma (RCC).

Treatment-naive patients of any prognostic risk category (N=915) were randomly assigned to an atezolizumab plus bevacizumab treatment arm or to a sunitinib arm; and were stratified by PD-L1 status.

IMmotion 151 met one of its two endpoints, with significantly improved PFS in patients with tumors expressing PD-L1. Median PFS was 11.2 months in the atezolizumab plus bevacizumab treatment arm versus 7.7 months in the sunitinib arm (hazard ratio, 0.74; [95% CI, 0.57–0.96]; P=.02). However, that association was not clearly supported using independent, blinded reviewer-assessed PFS, cautioned lead investigator Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York City.

The combination of atezolizumab plus bevacizumab is gaining momentum: In December 2017, Roche announced that this combination with chemotherapy in front-line NSCLC improved 12-month PFS in the Phase 3 IMpower150 study.

Results from the COLUMBUS study in melanoma
In melanoma, Array Biopharma’s binimetinib—a MEK inhibitor—in combination with encorafenib—a BRAF inhibitor—in patients with BRAF-mutant melanoma reduced the risk of death compared with vemurafenib (Zelboraf; Genentech) in the Phase 3 trial (hazard ratio 0.61, [95% CI 0.47, 0.79]; P<0.001).

The combination arm almost doubled median OS compared with vemurafenib: 33.6 months vs 16.9 months, respectively.

“This data suggest that the combination of encorafenib and binimetinib may have the potential to become a meaningful new therapy for patients with advanced BRAF-mutant melanoma,” said Keith T. Flaherty, M., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School.

These results come as a major win for Array, which in March 2017 pulled its New Drug Application (NDA) for binimetinib monotherapy in NRAS-mutant melanoma after results from the Phase 3 NEMO trial showed no difference in median OS when compared to standard-of-care chemotherapy.

Binimetinib monotherapy and binimetinib plus encorafenib remain under review for BRAF-mutant advanced, unresectable, or metastatic melanoma, with an FDA decision expected by June 30, 2018.

Lastly, in non-metastatic, castration-resistance prostate cancer
Finally, Janssen’s next-generation androgen inhibitor, apalutamide, showed a 72% reduced risk for metastasis or death compared with placebo among men with non-metastatic castration-resistant prostate cancer at high risk for developing metastatic disease.

In yesterday’s ASCO pre-GU Symposium press cast, Eric J. Small, MD, FASCO, professor of medicine at University of California, San Francisco, said, “To date there has been no therapy approved for this disease state, and the aim of this study was to see if the development of metastases in the transition from non-metastatic to metastatic could be slowed.”

In the Phase 3, SPARTAN trial, patients (N=1207) were randomized 2:1 to daily apalutamide or placebo, in addition to continuous androgen deprivation therapy (ADT). The primary endpoint was metastasis-free survival (MFS). The trial ended early when the interim analysis showed the primary endpoint had been met.

Median MFS in the apalutamide treatment arm was 40.5 months versus 16.2 months in the placebo arm, representing a 72% reduction in the hazard for metastatic progression or death.

Even though apalutamide was associated with a reduced risk of death, according to Dr. Small, “that was not significant at this early interim analysis and will continue to be followed. The trend was certainly encouraging,” he said.

The FDA granted priority review to apalutamide, with an estimated PDUFA date by April 11, 2018.

The apalutamide program is also being assessed in the Phase 3 TITAN trial, comparing apalutamide combined with ADT to ADT alone in metastatic, hormone-sensitive prostate cancer.


By Megan Garlapow

February 05, 2018 - 11:02 pm Posted in ASCO GU Conference Coverage comments0 Comments

On the eve of the 2018 Genitourinary Cancers Symposium to be held in San Francisco February 8-10, a pre-meeting presscast featured four noteworthy abstracts: two related to immunotherapy with a PD-L1 inhibitor atezolizumab in urothelial cancers and two to treatment of non-metastatic advanced prostate cancer.

PD-L1 Inhibitor Plus Anti-Angiogenesis Inhibitor in Metastatic Renal Cell Carcinoma

The combination of atezolizumab plus bevacizumab delayed cancer progression by 3.5 months compared with standard sunitinib in a Phase 3 trial of patients with previously untreated metastatic renal cell cancer. Patients whose tumors expressed PD-L1 had the most benefit. The side effects of atezolizumab plus bevacizumab were less severe compared with sunitinib.

“Because the side effects were decidedly less harsh, and the progression-free survival was better, this relatively easy-to-administer combination should be considered a first-line option for PD-L1-positive advanced renal cell carcinoma,” said lead author Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York City.

Dr. Motzer suggested that the rationale for combining atezolizumab, a PD-L1 inhibitor, with bevacizumab, an anti angiogenic agent, is that theoretically the combination could prime tumor and immune cells to respond to atezolizumab.

The Phase 3 IMmotion151 study enrolled 915 patients with untreated metastatic renal cell cancer and randomized them 1:1 to treatment with atezolizumab plus bevacizumab versus sunitinib, which has been standard of care for about 10 years. Patients were stratified for PD-L1 expression (<1% vs >1% on tumor infiltrating immune cells). Of the 915 patients, 362 were PD-L1-positive.

Among PD-L1 positive patients, median progression-free survival (PFS) was 11.2 months on the combination therapy versus 7.7 months on standard sunitinib, representing a 26% reduction in the likelihood of disease progression (P=.02).

Looking at the entire intent-to-treat cohort (n=915) of patients with all levels of PD-L1 expression, median PFS was 11.2 months for the combination versus 8.4 months for standard sunitinib, a 17% reduction in the likelihood of disease progression for the combination therapy (P=.0219).

Treatment-related grades 3-4 adverse events were reported in 40% of those treated with atezolizumab plus bevacizumab versus 54% of those in the sunitinib group.

“For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5 month longer PFS…. is an important development,” said Dr. Motzer.

Who Will Respond to Atezolizumab?

With five new immunotherapies FDA-approved for the treatment of urothelial cancers, it is important to identify which patients might gain the most benefit from these new and expensive drugs. Researchers have developed a model that appears to predict overall survival (OS) for people with advanced urothelial cancer treated with atezolizumab.

“We believe we have developed the first prognostic model that, once confirmed in larger studies, could provide a critical decision-making tool for clinicians,” stated lead author Gregory Pond, PhD, McMaster University, Hamilton, Ontario, Canada.

The model was based on data from the Phase 2 IMvigor210 clinical trial atezolizumab in 310 patients with advanced urothelial cancer that progressed on standard cisplatin chemotherapy, and then validated in 95 people with bladder cancer enrolled in a Phase 1 trial.

The researchers evaluated traditional factors associated with survival in patients with advanced bladder cancer treated with chemotherapy that included performance status, site of tumor, sites of metastasis, tumor stage, blood test results, smoking status, and prior treatments. They also assessed PD-L1 status, a marker for the efficacy of atezolizumab.

The six factors found to predict OS were:

  • ECOG performance status
  • Liver metastases
  • Elevated platelet blood count
  • Increased neutrophil-lymphocyte ration
  • Elevated lactate dehydrogenase
  • Hemoglobin <10 g/dl

The higher the number of these six prognostic factors, the worse the survival among these patients. In the IMvigor210 trial, median OS was 19.6 months for those with 0-1 factors; 5.9 months for those with 2-3 factors; and 2.6 months for those with 4 factors or more.

The authors plan to validate this model among different datasets and try to determine whether specific subgroups have an improved response to atezolizumab.

“It’s important to remember … that it is the minority of patients who have long-term responses [to immunotherapies] and we currently have no way of pinpointing who these patients are. As this study demonstrates, prognostic models may help us apply immunotherapy to patients who stand to derive the most benefit,” said ASCO Expert Sumanta K. Pal, MD, who moderated the presscast.

Moving Docetaxel Up to Non-Metastatic Advanced Prostate Cancer

A new analysis of the ongoing STAMPEDE trial showed that the addition of docetaxel to hormone therapy for advanced prostate cancer that had not metastasized improved quality of life (QoL) and reduced the need for subsequent therapy. A previous study showed that the addition of docetaxel reduced the risk of recurrence in this setting.

“We already knew that docetaxel prolongs survival for men with metastatic prostate cancer, but this improvement in quality of life and reduction in subsequent treatment, and therefore costs, in non-metastatic disease is somewhat surprising and may cause clinicians to re-think how and when they use docetaxel to treat prostate cancer,” said lead author Nicholas D. James, MD, PhD, University of Birmingham, U.K.

STAMPEDE is a very large trial that includes more than 9000 men with non-metastatic and metastatic advanced prostate cancer and to date, has evaluated 10 different drugs. An earlier analysis of STAMPEDE found that 592 men treated with docetaxel lived about 10 months longer versus men on standard hormonal therapy. The present analysis looked at health-related quality of life and cost-effectiveness of the addition of docetaxel and prednisolone to hormone therapy compared with hormone therapy alone (standard of care).

Participants rated five aspects of their health on a self-reporting tool called EuroQol EQ-5D: mobility, self-care, activities of daily life, pain levels, and anxiety and depression levels. Based on responses the authors modeled changes in predicted length of survival, quality-adjusted life years (QALY), and incremental cost-effectiveness.

For men with metastatic disease treated with docetaxel plus hormone therapy, predicted survival was 0.89 years longer compared with hormone therapy alone, and QoL was preserved for 0.51 years longer. For men with non-metastatic disease, predicted survival was 0.78 years longer and QoL was preserved for an additional 0.39 years with docetaxel plus hormone therapy versus hormone therapy alone.

The addition of docetaxel to hormone therapy was cost-effective for both non-metastatic and metastatic prostate cancer. The annual estimated cost of docetaxel in the U.K. is about 5000 British pounds (about $6750 dollars in the U.S.) per QALY gained. Dr. James and co-authors noted that the estimated cost of delaying or avoiding recurrence in the U.S. should be the same if not greater, due to higher drug prices in the U.S.

STAMPEDE is continuing to study newer drugs, including abiraterone. In the U.S., patients have a choice between abiraterone (an oral drug) and docetaxel, but docetaxel is about one fifth of the cost of abiraterone.

Apalutamide Delays Metastatic Prostate Cancer

There are no FDA-approved therapies for men with non-metastatic castrate-resistant prostate cancer (nmCRPC) following surgery or radiation plus androgen deprivation therapy (ADT). Some physicians advocate watchful waiting. But men with a rapidly rising PSA on ADT (doubling time of less than 8 to 10 months) are at significantly greater risk of developing metastases or death.

A new study shows that the oral androgen receptor inhibitor apalutamide reduced the risk of metastasis or death by 72% compared to placebo in men with nmCRPC; all patients were taking ADT.

“These data demonstrate that the use of apalutamide prior to the development of metastases clearly benefitted patients whose prostate cancer no longer responded to conventional hormonal therapy. It is exciting that there now exists such a well-tolerated agent for this group of high-risk patients for whom no approved therapies currently exist,” said lead author Eric J. Small, MD, University of California at San Francisco.

The SPARTAN study enrolled 1207 men with non-metastatic CRPC that stopped responding to ADT and were at high risk of metastasis with a PSA doubling time of 10 months or less and randomized them in a 2:1 ratio to receive oral apalutamide versus placebo added to ongoing ADT. When metastases developed, second therapies were added with an option to receive on-study abiraterone acetate plus placebo, a standard of care.

At entry, median PSA doubling time was 4.5 months in both arms. Apalutamide reduced the risk of metastasis and death by 72% compared with placebo and significantly prolonged median metastasis-free survival by 2 years (40.5 months in the apalutamide group vs 16.2 months in the placebo group, P<.001). Apalutamide significantly improved time to metastasis, PFS, and symptom progression compared to placebo.

Although it is too early to establish a survival benefit, a trend toward improved survival was observed for the apalutamide-treated group.

At a median follow-up of 20.3 months, 61% of the apalutamide group and 30% of the placebo group were still on therapy.

Apalutamide was well tolerated, and QoL scores were maintained when apalutamide was added to ADT.

“Until now, the optimal management of patients with prostate cancer and no visible evidence of spread with a rise in blood markers remained an enigma. These finding suggest that there may finally be a treatment that holds real promise for extending their health and their lives,” said Dr. Pal, presscast moderator.

By Adrian Barfield

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