The OBR Blog

October 22, 2012 - 09:10 am Posted in Featured comments0 Comments

Pharmaceutical companies continue to invest billions of dollars in new oncology treatments. With more than 900 cancer medications in the various pipelines at drug manufacturers and academic institutions, keeping abreast at how the oncology segment is progressing can be difficult. We thought it would be helpful to recap some of the highlights thus far in 2012, especially U.S. Food and Drug Administration (FDA) oncology-drug approvals for 2012 (Table 1). It is interesting to note that between novel new drugs and label expansions, 2012 is shaping up to be a good year for solid tumors and hematologic malignancies.

The most recent FDA oncology drug approval was announced October 12. Celgene Corporation’s Abraxane (nab-paclitaxel)already in use as a second-line therapy for metastatic breast cancer—was approved for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

The approval is based upon the results of a Phase 3 study where patients with advanced NSCLC received Abraxane plus carboplatin or paclitaxel plus carboplatin every three weeks. Meeting its primary endpoint, Abraxane demonstrated a statistically significant higher overall response rate for patients compared with those in the paclitaxel arm (33% vs 25%).

Also recently, on October 17 Eli Lilly announced that the FDA has approved their drug Alimta (pemetrexed) as a maintenance therapy following first-line Alimta plus cisplatin for locally advanced or metastatic nonsquamous NSCLC. The label inclusion was based on the results of Phase 3 data that demonstrated progression-free and overall survival advantages in the maintenance setting.

Medivation, Inc. and Astellas Pharma Inc. were also granted FDA approval for Xtandi capsules for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.  The FDA accepted the Xtandi NDA in July ‘12 and granted the filing Priority Review Designation with a PDUFA action date of November 22, 2012, and the FDA beat the clock with an approval in August.

Early this year in January, the FDA approved Pfizer’s drug Inlyta (axitinib) for patients with advanced kidney cancer (renal cell carcinoma) who have not responded to another drug for this type of cancer. However, on October 18, Pfizer announced Inlyta had missed its main late-stage study goal when compared with Onyx’s drug Nexavar in patients who had not been treated for renal cell carcinoma. Pfizer now needs to decide if they should study their drug in subpopulations of treatment naïve patients.

The highlights above are just a few of the exciting developments in oncology so far this year. Marqibo, Kyprolis, Xaltrap, and Perjeta all add to the armamentarium.

Supportive drugs FDA approved this year include Teva’s Neutroval (tbo-filgrastim). The drug is specifically approved to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

For the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain, the FDA approved Insys Therapeutics’ breakthrough cancer pain drug, Subsys (fentanyl sublingual spray), in January of this year.

See Table 1 below for a full listing of all the FDA approvals in oncology so far this year.

Table 1. FDA Approved Oncology Drugs 2012

Product Manufacturer Indication Date of Approval
Abraxane (paclitaxel) Celgene First-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. October 12, 2012
Pfizer, Inc. Chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy September 4, 2012
Stivarga (regorafenib) Bayer Healthcare Pharmaceuticals Patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. September 27, 2012
XTANDI (enzalutamide) Medivation, Inc. and Astellas Pharma US, Inc Patients with metastatic castration-resistant prostate cancer who have previously received docetaxel August 31, 2012
Novartis Pharmaceuticals Corp Pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected August 30, 2012
(vinCRIStine sulfate)
Talon Therapeutics, Inc Adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies August 9, 2012
Sanofi U.S., Inc. In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen August 3, 2012
Afinitor (everolimus) Novartis Pharmaceuticals Corporation Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole July 20, 2012
Kyprolis (carfilzomib) Onyx Pharmaceuticals Multiple myeloma patients who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy July 20, 2012
Erbitux (cetuximab) ImClone LLC, a wholly owned subsidiary of Eli Lilly and Co For use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use July 9, 2012
Therascreen KRAS RGQ PCR Kit QIAGEN Manchester, Ltd Concurrent with this cetuximab approval July 9, 2012
PERJETA (pertuzumab) Genentech, Inc In combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. June 8, 2012
VOTRIENT (pazopanib) GlaxoSmithKline Patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy April 26, 2012
Afinitor (everolimus) Novartis Adults with renal angiomyolipoma, associated with tuberous sclerosis complex (TSC), who do not require immediate surgery April 26, 2012
Gleevec (imatinib) Novartis Pharmaceuticals Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive Gastrointestinal Stromal Tumors (GIST). January 31, 2012
ERIVEDGE (vismodegib) Genentech, Inc Adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation January 30, 2012
Pfizer, Inc. Advanced renal cell carcinoma after failure of one prior systemic therapy January 27, 2012
Voraxaze (glucarpidase) BTG International Inc Toxic plasma methotrexate concentrations
(>1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function
January 17, 2012

And of course cancer progress is measured by more than just FDA approvals. In response to the critical drug shortage of doxorubicin, the FDA exercised its enforcement discretion for the temporary importation and distribution of Lipodox.

Although Lipodox is a drug with the same active ingredient, dosage, strength, and route of administration as Doxil, and Lipodox is manufactured in a facility that has been inspected by FDA and found to be in compliance with current good manufacturing practices, the drug is not FDA approved, and therefore, cannot be considered a generic equivalent of Doxil.

Temporary importation of foreign drugs is only considered by the FDA in cases when there is a shortage of an approved US drug that is critical to patients, and that manufacturer(s) of the approved US drug cannot resolve the shortage in the immediate future.

Impending Drug Approvals for the Remainder of the Year

Celgene Corporation was expecting an Oncologic Drugs Advisory Committee (ODAC) meeting for pomalidomide to take place on November 8, but the company recently announced that it was notified by the FDA that there will not be a meeting. Pomalidomide is being studied in combination with dexamethasone as a potential treatment for patients with relapsed and refractory multiple myeloma that has progressed following at least two prior therapies. Celgene was notified that the review of its New Drug Application (NDA) for pomalidomide is continuing with the previously announced Prescription Drug User Fee Act (PDUFA) action date Feb. 10, 2013.

At the end of August Exelixis Inc. announced that the FDA had notified them that cabozantonib had also been removed from the November 8 ODAC line-up. Cabozantinib is being studied as a treatment for patients with progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). The FDA also granted priority review designation to the NDA for cabozantinib. Exelixis announced top-line results in October ’11 from its EXAM study. Data from the study demonstrated that the primary endpoint of improving progression-free survival (PFS) was met. Compared with the placebo arm of the study, cabozantinib improved median PFS by 7.2 months (11.2 mo vs 4.0 mo). The PDUFA action date stays the same and is still November 29, 2012. MTC is considered an orphan disease.

Johnson & Johnson’s Janssen unit is seeking to broaden their Zytiga drug’s indication in combination with prednisone in metastatic castration-resistant prostate cancer. The sNDA was submitted in June; which means that the new indication could be approved in December 2012.

Table 2. Upcoming Market Events

Product Manufacturer Event Action Date
cabozantinib (XL184) Exelixis Inc. July 30th the FDA granted a priority review designation for cabozantinib, a potential treatment for medullary thyroid cancer (MTC). PDUFA action date is November 29, 2012.

Zytiga (abiraterone) Johnson & Johnson  Janssen Biotech FDA had granted an sNDA for Zytiga a priority review of six months.

The sNDA was submitted during June 2012; which means that the new indication could be approved in December 2012.

Other Developments and Upcoming Meetings

We’re also keeping on our eyes on the recent news that researchers can stratify breast cancer into 4 distinct genetic types of the disease and that some drugs already available to treat cancer in other parts of the body could possibly be used to treat certain forms of breast cancer that share the same genetic abnormalities. For instance, the researchers found triple negative breast cancer—a particularly aggressive disease—genetically resembles a form of ovarian cancer that is currently treatable.

Additionally, with the San Antonio Breast Cancer Symposium (SABCS) and American Society of Hematology (ASH) annual meeting just around the corner, OBR will be bringing you daily coverage of all the news coming out of the meetings. Stay tuned!

October 02, 2012 - 10:10 am Posted in Featured comments0 Comments

The speed of innovation continues to accelerate in metastatic melanoma and the battle between Roche/Genentech and GlaxoSmithKline (GSK) is heating up. GSK is looking to challenge Zelboraf® (vemurafenib), Roche’s BRAF inhibitor, with its own BRAF targeting molecule, dabrafenib. In addition to BRAF, GSK is looking to make an impact in melanoma with its first-in-class MEK inhibitor, trametinib. At ASCO 2012, GSK presented data from two Phase III trials; the BREAK-3 trial of dabrafenib versus dacarbazine (Hauschild, Abstract LBA8500), and the METRIC trial of trametinib versus chemotherapy (Robert, Abstract LBA8509). With both trials showing strongly positive data, GSK then gave a glimpse into the future of melanoma therapy with the interim results of a Phase I/II trial that examined the combination of dabrafenib plus trametinib in treatment naïve patients with metastatic melanoma (Weber, Abstract 8510). During the melanoma oral session this weekend at the annual ESMO meeting in Vienna, GSK presented updated data from the randomized Part C portion of the Phase I/II study (Long, Abstract LBA27). In this portion, 162 patients were randomized to receive either dabrafenib monotherapy (150 mg BID), or dabrafenib plus trametinib (150 mg BID/1 mg QD), or dabrafenib plus trametinib (150 mg BID/2 mg QD; “full dose”). Overall response rates were 54%, 50%, and 76%, respectively. Of note, in the full dose cohort, the CR rate was 9%. The median PFS was 5.8, 9.2 (HR=0.56, p=0.006), and 9.4 months (HR=0.39, p<0.0001). The rate of squamous cell carcinoma/keratoacanthoma was 7% in the full dose arm, compared to 19% in the dabrafenib alone arm.

In order not to get left behind, in the same melanoma session at ESMO Roche presented Phase Ib data of their own BRAF/MEK combination (Zelboraf plus GDC-0973). The trial included 10 different dosing cohorts as Roche attempted to optimize the regimen for their new combination. The maximum tolerated dose was Zelboraf 960 mg BID and GDC-0973 60 mg QD 21days on/7 days off. Across all doses (n=32), the combination showed reasonable activity in Zelboraf-pretreated patients with a 16% response rate (all partial responses) and a 66% disease control rate. However, the highlight of the presentation was the waterfall plot for the BRAF-inhibitor naïve patients. Although this was a small sample (25 patients), all patients showed benefit from the drug combination and the response rate was estimated to be 88% (Gonzalez, Abstract LBA28). Also, the three patients who did not achieve a partial response were just shy of the 30% reduction cut-off, according to the waterfall plot. With a response rate approaching 90% in this early study, Roche has plenty to be enthusiastic about.

Although data from such a small sampling of patients must be taken with a grain a salt, the contrast between GSK’s combination and Roche’s combination gets interesting when depth of response is considered with the ORR. There were no complete responses in the 25 patients who received Zelboraf plus GDC-0973, while the best response was about a 65% reduction in tumor burden. The impressive ~90% ORR with Roche’s combination is tempered by the fact that dabrafenib/trametinib demonstrated a 9% CR rate in the larger Phase II study. If all of this early data were to hold up in Phase III trials, it would be very interesting to see the marketing battle between a combination with higher response rate versus one with deeper responses.

GSK has a 5-month lead, starting two Phase III trials of dabrafenib/trametinib versus dabrafenib monotherapy and versus Zelboraf monotherapy back in April and May 2012 (NCT01584648 and NCT01597908, respectively). Roche just recently announced plans for a Phase III front-line study of their combination versus Zelboraf alone (NCT01689519), but the trial has yet to begin enrolling patients. In just a few short years melanoma has gone from an oncology afterthought to a crowded battleground; such rapid development should be encouraging to both patients and pharmaceutical companies alike.

By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health

October 02, 2012 - 10:10 am Posted in Featured comments0 Comments

Seven targeted agents are presently approved for use in renal cell carcinoma (RCC), including 5 approved for use in the first-line setting, of which 4 are VEGF pathway inhibitors. With such an abundance of treatment options and few differentiating factors, how is a physician (or patient) to choose the best course of therapy from? Efficacy is clearly of primary importance; however, many of these agents have yet to be compared in head-to-head trials. Toxicity is the next logical choice, as it can have a significant impact on treatment intensity and patient quality of life. So how does one (that is, a manufacturer with a new agent in RCC – or any other crowded market) go about demonstrating such differentiation?

Votrient® (pazopanib, GlaxoSmithKline) was approved based on demonstrated superior progression-free survival (PFS) benefit compared to placebo in treatment-naïve or cytokine-pretreated RCC. This superiority was sufficient for regulatory approval, but the lack of comparison to other approved agents relegated Votrient to minimal market share, primarily in later lines of therapy. In the absence of trial results from a direct comparison of Votrient with the market leader, Sutent® (sunitinib, Pfizer), physicians have been reticent to adopt Votrient upfront.

The eagerly anticipated results of the COMPARZ trial were reported in the Presidential Symposium at the 2012 European Society of Medical Oncology conference. COMPARZ was a global, Phase III non-inferiority trial that randomized 1100 patients to receive either Votrient or Sutent as front-line therapy for metastatic RCC. COMPARZ achieved its primary endpoint of PFS and demonstrated that Votrient was non-inferior to Sutent, with a hazard ratio for PFS of 1.047. Median PFS was 8.4 months for GSK’s Votrient compared to 9.5 months for Pfizer’s Sutent. Data on secondary endpoints were also presented demonstrating similar median overall survival between the two agents at 28.4 months for Votrient versus 29.3 months for Sutent; overall response rates were 31% and 25%, respectively. Votrient did have a somewhat better toxicity profile with less hematologic toxicity, hand-foot syndrome, peripheral edema, taste alteration, rash and fatigue, although patients treated with Votrient had worse hepatoxicity and weight loss.

Will similar efficacy coupled with a somewhat better toxicity profile of Votrient be enough to change physician’s prescribing habits in first line RCC? As Sutent is extremely well entrenched as the leader in this setting, it is difficult to believe that the COMPARZ trial, which demonstrated non-inferiority of Votrient results rather than superiority, will have much impact.

Perhaps in anticipation of this, GlaxoSmithKline also sponsored the PISCES patient preference study. The PISCES trial randomized patients to sequential treatment with Votrient (10 weeks) followed by Sutent (10 weeks) or the reverse order, and patients completed preference questionnaires at the end of each treatment period. This unique design allowed direct evaluation of drug preference among patients who had been equally exposed to both agents. PISCES results, which were presented in June 2012 at annual meeting of the American Society of Clinical Oncology (ASCO), were overwhelming – 70% of patients who completed both treatments and questionnaires preferred Votrient whereas only 22% preferred Sutent (8% stated no preference). Overall quality of life and all queried toxicities were cited as favoring Votrient, with fatigue standing out from the patients’ perspective. With COMPARZ data in hand, coupled with the overwhelming nature of the patient preference study favoring Votrient, will GSK be able to mount a successful marketing campaign against the market leader, Sutent?  A survey with U.S. community oncologists conducted in July 2012 suggested that 13% of oncologists expect to prescribe Votrient significantly more in light of the PISCES data and if COMPARZ demonstrated non-inferiority, and another 26% of physicians expect to prescribe Votrient somewhat more in this scenario1.  If this expected change in practice holds true, Sutent’s six-year domination streak could be coming to an end.  It will be extremely interesting to watch the battle for first-line play out and to see if patient preference can be successfully utilized to improve Votrient’s market share in this setting.

1. Kantar Health survey of 31 U.S. oncologists, conducted July 11-16, 2012.  Q4: How will the results of the PISCES trial affect your choice of agent for future first-line treatment of good / intermediate risk advanced or metastatic RCC: Patient preference favoring Votrient in conjunction with non-inferior PFS data from COMPARZ?

By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Greg Wolfe, PhD, Senior Consultant, Kantar Health

October 01, 2012 - 10:10 am Posted in Featured comments0 Comments

During the past few years, drug development for NSCLC has epitomized the term “personalized medicine,” as new patient segments are carved out. A clear example of this is Xalkori® (crizotinib, Pfizer), which targets patients whose tumors harbor EML4-ALK fusion proteins (“ALK+”). In the United States, Xalkori was granted an accelerated approval in August 2011 by the Food and Drug Administration based on results of a Phase I and a Phase II trial. Only recently has Europe acted: Xalkori received a positive opinion from the Committee for Medicinal Products for Human Use in August 2012.

In the second-stage of a two-stage Phase I trial, 116 ALK-positive patients were treated with Xalkori, which produced a response rate of 61%, a median progression-free survival of 10 months, and 81% overall survival at 12 months (Camidge, Abstract 2501, ASCO 2011). Retrospective comparison of this data for the subset of patients treated in the second-line to ALK-positive positive patients who were treated with other second-line chemotherapy suggested an overall survival advantage (Shaw, Lancet Oncol, 2011). The PROFILE 1005 Phase II study of 400 patients confirmed these data as 83% of patients exhibited target lesion shrinkage (Crinò, Abstract 7514, ASCO 2011). Based on these results, Pfizer initiated the Phase III PROFILE 1007 trial which compared Xalkori to Alimta® (pemetrexed, Eli Lilly) or docetaxel as a second-line therapy in ALK+ advanced NSCLC patients. It was announced in June that this trial achieved its primary endpoint by significantly improving progression-free survival (Pfizer press release, June 19, 2012) and ESMO 2012 offered the presentation of results from this first randomized trial of Xalkori (Shaw, Abstract 1LBA).

The data were impressive in spite of the hype. Compared to chemotherapy, Xalkori more than doubled progression-free survival (Intent-to-treat: 7.7 months versus 3.0 months, HR 0.49, p<0.0001). Subgroup analysis of the control arm indicated that Xalkori performed better than either Alimta (“As treated” population1: 7.7 months versus 4.2 months, HR 0.59, p=0.0004) or docetaxel (“As treated” population: 7.7 months versus 2.6 months, HR 0.30, p<0.0001). The response rate benefit seen in the earlier Phase I and II trials was confirmed (ORR: 65.3% versus 19.5%, p<0.0001).

The toxicities were expected based on those previously identified. Xalkori administration was associated with an increase in vision disorders, diarrhea, nausea/vomiting, altered liver chemistry, dysgeusia, edema and dizziness. Drug discontinuations were also higher in the Xalkori arm (17% versus 13%). This increased amount of adverse events is tempered by the fact that patients on the Xalkori arm were treated with drug longer: 11 versus 4 median cycles.

An interim analysis of overall survival suggested no survival benefit (20.3 months versus 22.8 months, HR 1.02, p=0.5394); however, the discussant to this presentation (Dr. Soria) noted that 87% of the patients on the control arm crossed over to Xalkori by entering the Phase II PROFILE 1005 trial and that 49% of the patients on the Xalkori arm are still on treatment compared to 16% of patients treated with control. Dr. Soria further put this result in perspective by noting that second-line treatment of Alimta had provided only a 9.3 month overall survival benefit (Hanna, J Clin Oncol, 2004). Therefore, the use of Xalkori is, as Dr. Soria noted, is “changing the natural history of the disease.” The lack of survival benefit is something being encountered more and more in oncology, and often the post-trial crossover to active drug is felt to be the primary culprit. While researchers and clinicians understand the confounding nature of crossover, and treatment ethics continue to support this practice, the FDA has yet to approve a drug in NSCLC based on PFS benefit without an overall survival benefit. PROFILE 1007 and the ongoing PROFILE 1014 trial in first-line NSCLC are meant to serve as confirmatory trials for Xalkori’s accelerated approval to be converted to full approval. Xalkori may be the first to challenge the FDA’s precedent of overall survival as the approvable endpoint in NSCLC, assuming that further follow-up continues to show no survival benefit in PROFILE 1007. Roche will soon be looking to pose a similar situation to the FDA with Tarceva’s pending regulatory filing for first-line EGFR mutant NSCLC, which also showed an impressive PFS benefit but lacked an overall survival benefit compared to chemotherapy (EURTAC trial; Rosell, Abstract 7503, ASCO 2011).

Today, Xalkori stands all alone, exultant; not only does it act on ALK+ patients, but it may act on other patient segments as well. The lead author of PROFILE 1007, Dr. Shaw, presented a paper at ASCO 2012 suggesting activity of Xalkori in patients whose tumors harbor ROS1 rearrangements (Abstract 7508, ASCO 2012). Given its kinase selectivity profile, one might expect Xalkori to be also tested as a cMet inhibitor (IC50 = 8 nM) and as a RON inhibitor (IC50 = 80 nM). However, competition in the ALK+ segment is lurking. There are several other candidate inhibitors in development. Results of a Phase I trial suggested that LDK378 (Novartis) has marked activity in ALK+ NSCLC, even in patients who have progressed on Xalkori (Shaw, Abstract 440O, ESMO 2012). Additionally, a Chugai / Roche compound, CH5424802, exhibited an 85% overall response rate in relapsed or refractory patients who had not received prior ALK inhibitor therapy (Nishio, Abstract 441O, ESMO 2012).

The “Profile” of Xalkori at ESMO 2012 has cemented the idea of pursuing personalized medicine. Together with the past data on the EGFR inhibitors in patients with EGFR activating mutations, no physician treating a NSCLC patient will reflexively reach for chemotherapy without thinking first of the unique molecular characteristics associated with each individual patient’s tumor.

1. “As treated” population excludes 1 patient in the experimental arm who did not receive crizotinib and 3 patients in the control arm who did not receive chemotherapy treatment

By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Arnold DuBell, PhD, Associate Consultant, Kantar Health

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