ROCKVILLE, MD—Just three weeks after the Oncologic Drugs Advisory Committee (ODAC) voted overwhelmingly to urge the FDA to approve the use of zoledronic acid (Zometa) for the treatment of bone metastases in patients with multiple myeloma, breast cancer, prostate cancer, lung cancer, and other solid tumors, the agency did grant the approval. This was the drug's second approved indication in six months.
At the ODAC meeting held here on January 31, there was remarkably little discussion and no argument.
According to Burkhard Daldrup, PhD, Global Head of Drug Regulatory Affairs in the Oncology Business Unit of Novartis Pharmaceuticals Corp., the drug's sponsor, Zometa belongs to a new class of highly potent bisphosphonates. Zometa was recently approved by the FDA for treatment of hypercalcemia of malignancy and is now being evaluated for non-oncologic uses (Paget's disease, osteoporosis, and rheumatoid arthritis) in addition to the present application.
Novartis's application for approval was based on three Phase III randomized, double-blind studies that, Dr. Daldrup said, constitute the largest trials ever conducted in bone metastasis.
“Zometa is bone specific, not tumor specific, and it is effective in a broad range of tumor types: breast cancer, multiple myeloma, prostate cancer, and other solid tumors,” he said. “Other bisphosphonates have not been effective in these tumors, and Zometa's safety, based on data from more than 3,000 patients, is comparable to that of intravenous pamidronate.”
Metastatic Bone Disease
The incidence of bone metastasis is very high in certain cancers, noted Robert Coleman, MD, of the Cancer Research Centre of Weston Park Hospital in Sheffield, England. It ranges from a low of 14 to 45 percent in melanoma to a high of 70 to 95 percent in multiple myeloma. Median survival without specific treatment for bone metastasis is six to 48 months, depending on the cancer.
“In addition, skeletal-related events [SREs] are a significant problem in metastatic bone disease,” Dr. Coleman continued. These include radiation to bone, fractures, hypercalcemia of malignancy, bone surgery, spinal cord compression, and bone pain. Traditional treatments, most of which will remain important for the foreseeable future, have included radiotherapy/radionuclides, endocrine treatment, chemotherapy, orthopedic intervention, and analgesics.
During preclinical testing, Zometa demonstrated advantages over pamidronate, its comparator in one of the clinical trials, Dr. Coleman said. “In vitro, it is a potent inhibitor of osteoclast formation and bone resorption”, regardless of the pathogenic stimulus. In vivo, it inhibits bone resorption in a variety of models of benign and malignant bone disease, irrespective of tumor type.
“It preserves bone architecture and strength, and it reduces the number and size of bone metastases in tumor-induced osteolysis. In addition, for reasons that we don't yet understand, it has anti-angiogenic and anti-pain effects.”
A Phase II study that compared Zometa with pamidronate established that a 4 mg dose given every four weeks produced sustained effects on serum and urinary markers of bone resorption, and the time to first SRE in breast cancer patients was almost two months longer with 4 mg than with 2 mg.
James Berenson, MD, of Cedars-Sinai Medical Center in Los Angeles, was the principal investigator in Trial 010 for breast cancer and multiple myeloma. It was a Phase III double-blind and double-dummy study, with a total of 1,640 patients, designed to demonstrate the effectiveness and safety profile of Zometa through a non-inferiority comparison with pamidronate.
The dosing regimen consisted of pamidronate at 90 mg every three to four weeks given in a two-hour infusion compared with Zometa at 4 mg and 8/4 mg every three to four weeks given in a 15-minute infusion. (The original 8 mg dose was reduced to 4 mg and the five-minute infusion increased to 15 minutes when three patients developed renal failure early in the study.)
Patients also received 400 IU of vitamin D and 500 mg of calcium because of the potential for microfractures—observed in animals but not in humans. The trial lasted for 13 months.
The primary endpoint was the percentage of patients experiencing any SRE except hypercalcemia of malignancy. Secondary endpoints included time to first SRE, skeletal morbidity rate, pain/analgesia scores, bone lesion response, and time to disease progression.
By the end of 13 months, 44 percent of patients receiving 4 mg of Zometa experienced an SRE, compared with 46 percent of 8 mg patients and 46 percent of patients receiving pamidronate. The vast majority of the fractures were related to bone radiation (15%, 21%, and 20%, respectively for the three study arms). A much smaller number of SREs were due to bone surgery (4%, 3%, and 6%), and an even smaller number of spinal cord compressions. The time to first SRE was virtually identical for all three groups.
Dr. Berenson told the members of ODAC that the breast cancer and multiple myeloma quality-of-life endpoints were comparable for Zometa and pamidronate with regard to time to bone metastasis and disease progression, pain and need for analgesia, Eastern Cooperative Oncology Group (ECOG) performance status, and global quality of life.
There was a wide variety of adverse events, Dr. Berenson said, the most common of which were pyrexia, arthralgia, and anorexia.
Among Grade 3–4 events, six percent of patients in all treatment groups experienced anemia, and 10 percent in all groups had electrolyte and mineral adverse events (hypophosphatemia and hypo- and hyperkalemia).
The survival rate, again, was virtually identical for all three groups, with the majority of deaths related to the cancer. A smaller number of patients died of respiratory, thoracic, or cardiac problems.
Dr. Berenson summarized the results of Trial 010 by saying, “Zometa 4 mg via 15-minute infusion was comparable in safety and efficacy to pamidronate 90 mg over 120 minutes in treating bone metastasis in breast cancer and osteolytic lesions in multiple myeloma.”
Grant Williams, MD, Medical Team Leader for the FDA Division of Oncology Drug Products, noted but did not disparage the fact that Study 010 combined data from myeloma and breast cancer. He said that in the process of drug approval, the agency may take into account efficacy evidence from one indication that supports another. “It's a matter of science and judgment,” he said.
Dr. Williams also remarked that it is difficult to evaluate drugs for cancer-related morbidity because endpoints are affected by the dropout rate, and there is a problem of competing risks. He added that the agency found no evidence of bias between the arms in this study, but still, it could take issue with a claim of efficacy based on a single trial of non-inferiority design.
Nevertheless, he said, Study 010 did demonstrate efficacy, and he noted that other data support the application for approval.
Members of ODAC agreed unanimously (with one abstention) that Zometa retained at least 49 percent of pamidronate's efficacy—which had previously been demonstrated in comparison with placebo. They also agreed unanimously that there was substantial evidence that this study was adequate and well controlled.
Matthew Smith, MD, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston, was principal investigator of Study 039, which compared Zometa with placebo in prostate cancer.
Dr. Smith explained that in placebo-controlled trials, the objective is to demonstrate that Zometa is superior to placebo in treating bone metastasis. The primary and secondary endpoints were the same as Study 010.
The patients in Study 039 averaged 71 years of age, all had prostate cancer with documented bone metastasis, none was taking strong opiate analgesics, and all had an adequate ECOG performance status.
There were three treatment arms: 214 patients taking Zometa at 4 mg (37.9% of whom completed the study); 221 patients taking Zometa at 8/4 mg (28.1% completed); and 208 on placebo (31.3% completed). The major reason for discontinuation was death, adverse events, withdrawal of consent, and unsatisfactory therapeutic effect.
Thirty-three percent of patients in the Zometa 4 mg group experienced an SRE, as did 38 percent of the Zometa 8/4 mg patients and 44 percent of the placebo group. When fractures were excluded, Zometa 4 mg compared with placebo demonstrated significant efficacy, Dr. Smith said.
The time to first SRE was 214, 221, and 208 days, respectively, for the three study arms. Time to progression for bone lesion was 92 days for the Zometa 4 mg arm, 89 days for Zometa 8/4 mg, and 87 days for placebo. Time to disease progression was 84 days for all three groups.
Dr. Smith said that the primary cause of death within 28 days after study drug termination was mainly cancer related, but some patients died of respiratory, thoracic, or cardiac events. Survival time was not significantly different for the three arms.
The most frequently seen adverse event, by far, was bone pain, but there also was nausea and vomiting, constipation, fatigue, anemia, myalgia, weakness, and anorexia, among others. Among Grade 3–4 adverse events, 10 percent of all patients experienced anemia, and two percent in all three arms had electrolyte and mineral adverse events (hypocalcemia and a slightly higher incidence of hypophosphatemia and hypermagnesemia in the two Zometa arms).
Dr. Smith summed up Study 039 by telling the committee that Zometa decreases skeletal complications in men with prostate cancer and bone metastasis, it has an acceptable safety profile, and the risk of renal deterioration was no greater with Zometa than with placebo.
Amna Ibrahim, MD, FDA reviewer, asked ODAC to evaluate how convincing Study 039 was. Dr. Ibrahim said that the agency agreed with the sponsor's data and summarized the trial results by saying that the percentage of patients with SRE and the time to first SRE were significantly better for Zometa 4 mg than for placebo. For patients on the 8/4 mg arm, there was no difference compared with placebo.
The members of ODAC agreed. They voted unanimously that Study 039 provides supportive evidence for Zometa's efficacy in prostate cancer, and they voted almost unanimously (one against) that this was an adequate and well-controlled trial.
Dr. Coleman described Study 011, which compared Zometa and placebo in solid tumors other than prostate and breast cancer. The same dosages of Zometa were used in this trial as in the other two, and the 773 patients, divided approximately evenly among the three arms, were 61 years old on average and predominantly (65%) male.
All patients were required to be on appropriate antineoplastic therapy, all had to have a serum creatinine level of no more than 3.0 mg/dL, and all had an adequate ECOG performance status. The study endpoints were time to progression of bone lesion as well as the malignant disease.
Thirty-eight percent of patients on Zometa 4 mg and 35 percent on 8/4 mg had an SRE while on study, compared with 44 percent of patients on placebo. The time to first SRE was 107 days for 4 mg Zometa, 99 days for 8/4 mg, and 81 days for placebo. The most common SRE was radiation to bone, then all fractures, surgery to bone, and spinal cord compression.
Of the patients who discontinued participation before completion of the study (an average of 74 from each arm), the majority died. Others stopped because of adverse events, withdrawn consent, or unsatisfactory therapeutic effect.
The results were as follows: for 4 mg Zometa, the mean time to bone lesion progression was 145 days and time to disease progression was 89 days. For the Zometa 8/4 mg arm, it was 238 and 91 days, respectively, For placebo, it was 0.34 days and 0.117 days, respectively. Survival was virtually the same for all three arms.
The types of adverse events were the same as for Studies 010 and 039. In terms of Grade 3–4 hematologic, electrolyte, and mineral changes, the incidence of anemia was less than five percent for all groups, with a slightly higher incidence for the Zometa groups. The incidence of hypocalcemia was less than two percent for all treatment groups, with a higher incidence of hypophosphatemia for Zometa.
Dr. Coleman concluded his presentation by acknowledging that certain adverse events were reported more frequently in the Zometa arms of the study and that the risk of renal deterioration was moderately higher in the 4 mg Zometa treatment group (with a 15-minute infusion) than in the placebo group. Nevertheless, he said, “Zometa is the first bisphosphonate to demonstrate efficacy in decreasing skeletal complications in a broad range of solid tumors”, and in the 4 mg dose it has a safety profile similar to pamidronate.
Dr. Ibrahim said that the FDA “could find no statistical significance for the 4 mg dose of Zometa for either of the two endpoints specified in the protocol, although there was substantial evidence for the 4 mg dose in time to first SRE, as well as substantial efficacy for the 8 mg dose in both specified endpoints.”
Nancy S. Scher, MD, FDA reviewer, talked about safety issues. She noted that the dose was reduced from 8 mg to 4 mg and the infusion time increased from five to 15 minutes after the three incidents of renal failure. As a result, the FDA instituted a requirement of creatinine monitoring of all patients. Dr. Scher reiterated the sponsor's safety data and concluded that in general, Zometa's safety profile was adequate—as long as renal function is monitored.
The members of ODAC agreed unanimously (with one abstention) that the results of Study 011 provided substantial evidence of efficacy for Zometa at 4 mg in patients with solid tumors other than breast and prostate cancer. The group also agreed, this time with no abstentions, with the sponsor's proposed indication: treatment of osteolytic, osteoblastic, and mixed bone metastases of solid tumors.
The current members of the Oncologic Drugs Advisory Committee are: Chairman, Stacy R. Nerenstone, MD, Oncology Associates, Helen & Harry Gray Cancer Center, Hartford (CT) Hospital; Executive Secretary, Karen M. Templeton-Somers, PhD, FDA; Kathy S. Albain, MD, Loyola University Medical Center Cancer Center, Maywood, IL; George W. Sledge, Jr., MD, Indiana University School of Medicine, Indiana Cancer Pavilion; Douglas W. Blayney, MD, Wilshire Oncology Medical Group, Pasadena, CA; David P. Kelsen, MD, Memorial Sloan-Kettering Cancer Center, New York City; Scott M. Lippman, MD, University of Texas MD Anderson Cancer Center, Houston; Donna Przepiorka, MD, PhD, Baylor College of Medicine, Houston; Bruce G. Redman, DO, University of Michigan Comprehensive Cancer Center; Ann Arbor; Sarah A. Taylor, MD, University of Kansas Medical Center, Kansas City; Otis W. Brawley, MD, Emory University School of Medicine, Atlanta; Stephen L. George, PhD, Duke University Medical Center, Durham, NC; and Consumer Representatives Jody L. Pelusi, FNP, PhD, Phoenix Indian Medical Center; and John T. Carpenter, Jr., MD, University of Alabama at Birmingham.
Also at this meeting of the Committee were voting consultant Derek Raghavan, MD, PhD, University of Southern California Norris Comprehensive Cancer Center, Los Angeles; nonvoting guest speakers Philip Bonomi, MD, Rush Medical Center, Chicago; and Patrick J. Loehrer, MD, Indiana University School of Medicine, Indiana Cancer Pavilion; and voting patient representative Eugene J. Kazmierczak, Crofton, MD.
Smoking Down Among the Young
A survey conducted by the Department of Health and Human Services and the University of Michigan Institute for Social Research had some encouraging news for anti-smoking advocates. It found that in the five years between 1996 and 2001, there was a 9% drop in the percentage of eighth graders who smoke.
The numbers were down for other grades as well. The percentage of 10th grade smokers fell from 30 percent to 21 percent. Among 12th graders, the percentage went from 37 percent to 30 percent between 1997 and 2001.
This welcome news contrasts sharply with the rise in teen smoking that was documented in the early 1990s
Higher cigarette costs, the success of anti-smoking campaigns targeted to young people, and limits placed on tobacco advertising as part of the settlement of a lawsuit brought by the state and federal governments against the industry have all played a part in bringing about the decline. Another important factor is peer pressure brought against young smokers by their contemporaries, many of whom no longer consider tobacco use to be socially acceptable.