Preliminary Evidence Suggests Intermittent Dosing Can Overcome Resistance to Vemurafenib in Melanoma

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.

Clinical Pearls

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

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Myeloma

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)

Jesùs F. San-Miguel, MD, PhD

Breast Cancer

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

Melinda L. Telli, MD

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

Gastrointestinal (Noncolorectal) 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

Daniel D. Von Hoff, MD

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

Roy S. Herbst, MD, PhD

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.

Suzanne L. Topalian, MD

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.

Lung Cancer

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

Mark A. Socinski, MD

Overall survival was not significantly different in any of the age subgroups. PFS was significantly longer in pemetrexed arm overall and for patients ≤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)

David R. Spigel, MD

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.

Prostate Cancer

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)

Genitourinary (Nonprostate) Cancer

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.

Gynecologic Cancer

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.

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View all coverage from the 2013 ASCO Meeting

Darrin Stuart, PhD

Results of a preliminary study presented at AACR 2013 suggest that using an intermittent dosing strategy with vemurafenib instead of continuous dosing has the potential to overcome the development of resistance in patients with melanoma treated with the drug.

&ldquo;When vemurafenib was introduced, it was exciting to witness the translation of the discovery of BRAF mutations in melanoma into an effective therapy. However, it was disappointing to see patients stop responding to such a promising therapy after 6 to 8 months of treatment,&rdquo; said Darrin Stuart, PhD, senior research investigator at the Novartis Institutes for Biomedical Research in Emeryville, California.

BRAF mutations occur in more than 50% of melanoma patients, and vemurafenib extends survival for these patients. However, most of these patients will relapse with lethal drugresistant disease, Stuart said.

A previous study by Stuart and colleagues found that xenografts of melanoma tumors expressing BRAF mutations implanted in experimental mouse models developed resistance to vemurafenib; moreover, the tumors exhibited dependence on vemurafenib to sustain their growth. When the drug was stopped, tumor growth was suspended, and some tumors regressed in the mouse model.

Stuart and colleagues sought to determine whether the tumor drug dependency observed in experimental animal models was also present in humans. They studied 42 patients with vemurafenibresistant tumors. CT scans were available for 19 of these patients who were taken off treatment; 14 of the 19 demonstrated a decrease in the rate of tumor growth once they were no longer taking vemurafenib.

&ldquo;This is the first evidence that the drug-addicted state that we observed in mouse models may also occur in humans,&rdquo; he said.

The next step was to implant xenografts of patient-derived BRAF-positive tumors in mice and treat them with vemurafenib either on an intermittent schedule of 4 weeks on/4 weeks off, or on continuous treatment. None of the animals in the intermittent dosing group developed drug resistance.

Continuous dosing maintained the selective pressure required for the few surviving tumor cells to develop resistance, and alternating the selective pressure through intermittent dosing appeared to prevent the evolution and expansion of resistant cells, Stuart said.

At a press conference, Stuart was asked whether the next step for Novartis will be to study intermittent dosing and compare it with continuous dosing in patients. &ldquo;Novartis is interested in testing multiple approaches that include trying different dosing regimens to using different combinations of drugs with vemurafenib,&rdquo; he said. &ldquo;I am not at liberty to say what the company is planning, but I can say we are enthusiastic about the findings I reported at this meeting. Patients derive a clinical benefit from vemurafenib and then develop resistance. Some sort of drug holiday makes sense. I hope people will study this clinically.&rdquo;

Reference

Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-144.