Michael J. Morris, MD

Michael J. Morris, MD, clinical director of Genitourinary Medical Oncology Service and Prostate Cancer Section head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discusses the safety and clinical activity of atezolizumab (Tecentriq) plus radium-223 dichloride (Xofigo) in patients with second-line metastatic castration-resistant prostate cancer (mCRPC).

Morris says the most important part of the phase 1b trial results were the immunotherapy-related adverse effects (AEs) observed, some of which were significant. There were 2 grade 5 events related to atezolizumab. The AEs observed were toxicities normally seen with this type of treatment, such as autoimmune hepatitis and autoimmune myositis. There were some patients with count reductions and neutropenia, which may have been caused by radium-223.

In terms of a countervailing clinical benefit, they did not see anything unexpected with either radium-223 or atezolizumab independently, according to Morris. Radium-223 does not independently significantly decline prostate-specific antigen levels, and there was no improvement observed in that way with the addition of atezolizumab. There were 3 patients who had significant and durable radiographic responses: 1 patient’s response lasted 192 days, another’s for 275 days, and the last for 337 days.

However, these responses were out of 44 patients total. Morris explains that they didn't believe they could identify who those patients were that responded, which has frequently been a problem in terms of immunotherapy and prostate cancer. They felt the toxicity to clinical benefit ratio did not warrant pushing the combination forward.

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Michael J. Morris, MD, discusses the safety and clinical activity of atezolizumab plus radium-223 dichloride in patients with second-line metastatic castration-resistant prostate cancer.

Phase1b Trial Investigates Atezolizumab and Radium-223 in mCRPC

Michael J. Morris, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, explains the rationale behind TAX 3503 (hormonal therapy +/- docetaxel for patients at high risk of metastatic prostate cancer).

ECOG 3805 looked at chemohormonal therapy versus hormonal therapy for patients with hormone-sensitive, newly metastatic prostate cancer.

TAX 3503 takes the question asked in early metastatic disease and moves it back one more step: to the pre-metastatic, high-risk population.

TAX 3503 analyzed patients at high risk of having metastatic disease. Patients were randomized to 18 months of hormonal therapy alone or in combination with docetaxel.

The Rationale of the TAX 3503 Trial in Prostate Cancer

Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses two important trials in breast cancer looking at extended hormonal therapy.

It is understood now that 10 years of tamoxifen is superior to 5 years in premenopausal patients with high-risk, early-stage disease. However, Tripathy says, most patients are postmenopausal and see benefit when treated with aromatase inhibitors. The question remains as to whether these patients could see benefit when treated with 10 years of an aromatase inhibitor compared to 5 years.

While these results may not be the most scientifically interesting, Tripathy says, they will surely affect many patients.

For patients who are premenopausal with high-risk, early-stage breast cancer, 10 years of tamoxifen has shown superiority to 5 years of tamoxifen

In postmenopausal women, aromatase inhibitors have demonstrated superiority and a better side effect profile

Two large studies look to answer the question as to whether extended use (10 years) of aromatase inhibitors will show benefit compared to 5 years

MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM)

Pomalidomide + LoDEX significantly extended PFS and overall survival vs. HiDEX in patients who failed lenalidomide and bortezomib. Pomalidomide + LoDEX should become a standard of care in relapsed/refractory multiple myeloma patients who have exhausted treatment with lenalidomide and bortezomib.

PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and carboplatin plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer

Preoperative gemcitabine and carboplatin plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.

Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates

Developmental Therapeutics - Immunotherapy

MPACT was a large, international study performed at community and academic centers. nab-paclitaxel + gemcitabine was superior to gemcitabine across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens.

A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors

MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A.

Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.

Nivolumab produced sustained survival with a manageable long-term safety profile in advanced melanoma, NSCLC and renal cell carcinoma, supporting its ongoing clinical development in controlled phase III trials with survival endpoints.

A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic and colorectal cancers

Preliminary results with NPC-1C show signs of clinical activity based on stable disease in heavily pretreated patients with pancreating and colorectal cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy.

A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results

Overall survival was not significantly different in any of the age subgroups. PFS was significantly longer in pemetrexed arm overall and for patients &le;70, but was similar for patients >70, >75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)

Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A.

CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer

The primary endpoint is overall survival; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The accrual goal is 600 patients randomized.

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.

In the phase III AFFIRM trial, patients with lung mCRPC had higher median overall survival than patients with liver mCRPC. Enzalutamide resulted in higher response rates in both liver and lung mCRPC patients. Overall survival and radiographic progression-free survival were also improved in both patient groups treated with enzalutamide.

Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization.

Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.

Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib

Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study).

The primary endpoint of this study is to evaluate if total PFS of sorafenib followed by pazopanib is non-inferior to pazopanib followed by sorafenib.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients with advanced or metastatic renal cell carcinoma previously treated with antiangiogenic therapy.

The primary endpoint is overall survival. Secondary endpoints include PFS, ORR, OR duration, adverse events, overall survival in PD-L1 positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling patients.

A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).

The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in folate receptor positive patients. Secondary objectives include overall survival, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing.

Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.

The results point out the potential importance of nibrin expression in the clinical outcome of patients with advanced ovarian cancer. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted.

Michael J. Morris, MD, medical oncologist, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, comments on the use of biomarkers in prostate cancer clinical trials.

The Uses of Biomarkers in Prostate Cancer Trials

Michael J. Morris, MD, medical oncologist, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, discusses an ongoing phase I/IIa study looking at radium-223 with docetaxel in patients with bone metastasis from castration-resistant prostate cancer (CRPC). Dr. Morris is an investigator in the trial.

There are two ways to treat patients with metastatic CRPC: by targeting the cancer cell itself and by targeting the host organ where most of the metastases reside (in the bone). This investigational treatment regimen does both: the chemotherapy targets the cancer while radium-223 targets the host organ.

First, Morris says, there is a need for a safety-based study to establish the best combination of doses and schedules. Currently, researchers are moving to the expansion cohort in which all patients are randomized to receive both drugs or docetaxel alone in order to compare safety profiles. This trial is actively accruing and will be presented at the 2013 American Society of Clinical Oncology meeting.

This investigational treatment regimen targets the cancer cells with chemotherapy and the host organ (bone) with radium-223

Currently, patients are being randomized to receive both drugs or docetaxel alone to compare safety profiles of chemotherapy alone and chemotherapy plus radium-223

This trial is accruing and will be presented at the 2013 ASCO meeting

Morris MJ, Hammers HJ, Sweeney C, et al. Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study.

Michael J. Morris, MD, discusses an ongoing phase I/IIa study looking at radium-223 with docetaxel in patients with bone metastasis from castration-resistant prostate cancer.

Author | Michael J. Morris, MD

Articles

Phase1b Trial Investigates Atezolizumab and Radium-223 in mCRPC

The Rationale of the TAX 3503 Trial in Prostate Cancer

The Uses of Biomarkers in Prostate Cancer Trials

Using Radium-223 Plus Docetaxel in Patients With Bone Metastasis From CRPC