A supplemental new drug application (sNDA) has been submitted to the FDA for cabozantinib (Cabometyx) for previously untreated patients with advanced renal cell carcinoma (RCC), according to Exelixis, the developer of the multikinase inhibitor.

The sNDA is based on the phase II CABOSUN trial, in which cabozantinib reduced the risk of progression or death by 34% versus sunitinib as a first-line treatment for patients with metastatic RCC. The median PFS was 2.6 months longer with cabozantinib versus sunitinib, at 8.2 versus 5.6 months (HR, 0.66; 95% CI, 0.46-0.95; 

“All of us at Exelixis are focused on improving care and outcomes for patients with cancer. Having successfully launched Cabometyx for patients with previously treated advanced RCC, the submission of this sNDA for Cabometyx as a treatment in the first-line RCC setting represents an important milestone for us,” Michael M. Morrissey, PhD, Exelixis president and CEO, said in a statement.

“If approved, Cabometyx will offer an important new alternative for the treatment of patients with previously untreated advanced RCC, having demonstrated a clinically meaningful and statistically significant progression-free survival benefit over sunitinib, a current standard of care. We would like to sincerely thank the study patients and clinicians who participated in the CABOSUN trial, the Alliance and NCI-CTEP, as well as our dedicated clinical, medical and regulatory teams for bringing us one step closer to our goal of expanding the population of patients who may benefit from Cabometyx.”

From July 2013 and April 2015, researchers randomly assigned patients to 60 mg daily of cabozantinib (n = 79) or 50 mg daily of sunitinib (n = 78) for 4 weeks on followed by 2 weeks off. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0 to 2, and had to be intermediate or poor risk per the IMDC criteria. Prior systemic treatment for RCC was not permitted.

Median age across the entire patient population was 63 years (range, 31-87), 78% of patients were male, and 92% were white. Thirty-six percent of patients had bone metastases and 75% of patients had prior nephrectomy. Patients had an ECOG performance status of 0 (45.9%), 1 (41.4%), or 2 (12.7%).

Median overall survival was 30.3 months in the cabozantinib arm versus 21.8 months in the sunitinib arm (HR, 0.80; 95% CI, 0.50-1.26). Cabozantinib was also superior for overall response rate, at 46% versus 18%.

In 87% of the cabozantinib arm, there was some reduction in target lesions, compared with 44% of the sunitinib cohort. The stable and progressive disease rates were 33% versus 36% and 18% versus 26%, respectively.

Adverse events (AEs) of any grade occurred in approximately 99% of each arm. The most common all-grade AEs with cabozantinib versus sunitinib included fatigue (85.9% vs 81.9%), hypertension (80.8% vs 68.1%), diarrhea (71.8% vs 52.8%), increased AST (61.5% vs 31.9%), and increased ALT (55.1% vs 27.8%).

Grade ≥3 AEs occurred in 66.7% of the cabozantinib arm versus 68.1% of the sunitinib arm. Common grade ≥3 AEs included diarrhea (10.3% with cabozantinib vs 11.1% with sunitinib), fatigue (6% vs 15%), hypertension (28.2% vs 22.2%), palmar-plantar erythrodysesthesia (7.7% vs 4.2%), and fatigue (6.4% vs 15.3%).

Patients in the cabozantinib arm were more likely to require dose reductions, 58% versus 49%. There were 16 AE-related discontinuations in each arm.

Cabozantinib is approved by the FDA as a treatment for patients with advanced RCC who have received prior antiangiogenic therapy.

Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. 

2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398.

Articles

A supplemental new drug application has been submitted to the FDA for cabozantinib for previously untreated patients with advanced renal cell carcinoma.

FDA Approval Sought for Frontline Cabozantinib in RCC

Anita T. Shaffer is your lead editorial contact for 

®, a twice monthly clinical news publication. A 10-year veteran of MJH Life Sciences™, she has been at the helm of the publication since shortly after joining the company in 2010. Before becoming an oncology journalist, she held a variety of editorial positions at The Times of Trenton, including metro editor. Email: anitashaffer@onclive.com

Less than 2 years after checkpoint blockade immunotherapy first became available for patients with non—small cell lung cancer (NSCLC), the PD-1 inhibitor pembrolizumab (Keytruda) is poised to reshape the treatment paradigm for previously untreated individuals without molecular mutations.

On May 10, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression, based on a cohort from the KEYNOTE-021 study.

 The decision amplifies the frontline role for the drug following the FDA’s October 2016 approval for pembrolizumab monotherapy in patients with metastatic NSCLC with greater than 50% PD-L1 expression as a result of the KEYNOTE-024 trial.

The expanded indications make pembrolizumab part of the first-line treatment considerations for the estimated 80% of patients with NSCLC whose tumors do not harbor 

 rearrangements, and cap a rapid rise for antibodies that target the PD-1/ PD-L1 pathway in NSCLC (Timeline). Looking forward, researchers are anticipating results from randomized phase III combination trials involving checkpoint blockade agents.

Timeline. FDA Checkpoint Immunotherapy Approvals in NSCLC

“This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non—small cell lung cancer, irrespective of PD-L1 expression,” Corey J. Langer, MD, principal investigator on the pivotal KEYNOTE-021 trial, said in a statement. “Physicians should continue to use each patient’s individual characteristics—including biomarker status, histology, and other clinical factors&mdash;to determine the best treatment plan for each person.” The evolving role of checkpoint blockade immunotherapy has been evident since the approval of pembrolizumab monotherapy. “As of October 2016, we saw a major shift in the therapeutic landscape in advanced NSCLC,” Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, said in an interview with OncologyLive® that took place before the latest approval. “KEYNOTE-024, at least in individuals with 50% or higher expression, documented a clear-cut outcome advantage for pembrolizumab versus standard platinum-based chemotherapy combinations.”

Findings from the phase II KEYNOTE-021 cohort study are scheduled to be updated at the 2017 American Society of Clinical Oncology Annual Meeting (Abstract 9094). In the trial, 123 patients were randomized to receive pemetrexed and carboplatin alone (n = 63) or in combination with pembrolizumab (n = 60). In the investigational arm, pembrolizumab was continued for 24 months.

In data submitted for the FDA’s approval, the pembrolizumab triplet elicited an objective response rate (ORR) of 55% compared with 29% with the chemotherapy agents alone (P = .0032). The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; 

After 10.6 months of follow-up, 88% of those in the pembrolizumab arm remained alive and progression free compared with 78% for the chemotherapy agents alone. The median time to response was 1.5 months with pembrolizumab compared with 2.7 months for the chemotherapy agents alone. Overall, a response of at least 6 months was seen for 92% of patients in the pembrolizumab group compared with 81% of those in the control arm.

The 6-month PFS rate was 77% with pembrolizumab (95% CI, 64-86) compared with 63% for chemotherapy alone (95% CI, 49-74). At the time of the analysis, 78% of patients remained alive in each arm, with no discernible differences in survival between the 2 groups (HR, 0.90; 95% CI, 0.42-1.91; 

 = .39). The 6-month overall survival (OS) was 92% in both arms. However, this analysis was likely confounded by crossover, since 74% of patients in the chemotherapy alone arm went on to receive a subsequent PD-1 or PD-L1 inhibitor compared with none in the pembrolizumab arm.

In assessments of PD-L1 staining, those with expression of less than 1% had an ORR of 57% with the pembrolizumab combination (12 of 21) compared with 13% in the chemotherapy arm (3 of 23). In those with expression on greater than 1% of cells, the ORR was 54% with pembrolizumab and chemotherapy (21 of 39) compared with 38% in the chemotherapy-alone arm. The ORRs were 80% and 35% in those with ≥50% expression for the pembrolizumab (16 of 20) and chemotherapy arms (6 of 17), respectively.

The role of PD-L1 as a biomarker in NSCLC remains an unanswered question since patients with low or no expression have responded to checkpoint blockade therapy. Langer said approximately one-third of patients in clinical trials have PD-L1 expression levels ≥50%, one-third are between 1% and 50%, and one-third are at <1%. “That’s been a consistent theme across clinical trials in terms of where expression levels generally end up,” he said.

Langer said PD-L1 expression is “an imperfect biomarker” but that it is becoming integrated into diagnostic workups. “PD-L1 testing is here to stay,” he said. “It’s been very helpful in my institution. Now it’s reflex—the pathologists will do it automatically the same way they would obtain ER [estrogen receptor] and PR [progesterone receptor] testing in breast cancer.”

Other considerations in the combination immunotherapy regimens involve toxicities, Langer said. In terms of adverse events (AEs), the incidence of grade 3 or higher treatment-related AEs was higher in the pembrolizumab plus chemotherapy group (39%) than in the chemotherapy-alone group (26%).

Frequently observed all-grade treatment-related AEs in the pembrolizumab and chemotherapy arms, respectively, included fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), and decreased appetite (31% vs 23%). AEs led to treatment discontinuations for 10% of those in the pembrolizumab arm versus 13% in the control group.

The most common grade ≥3 treatment-related AEs were decreased lymphocytes (23% with pembrolizumab vs 28% with chemotherapy alone), hemoglobin decreased (17% vs 19%), decreased neutrophil count (14% vs 8%), and platelets decreased (9% vs 10%).

The accelerated approval for pembrolizumab in combination with chemotherapy is contingent on results from a confirmatory trial.

The phase III KEYNOTE-189 study is currently exploring platinum-based chemotherapy plus pemetrexed with or without pembrolizumab for patients with untreated nonsquamous NSCLC. In this study, investigators will be able to choose between cisplatin or carboplatin as their platinum-based chemotherapy. The primary endpoint is PFS, with an accrual goal of 570 patients and an estimated completion date of March 2019 (NCT02578680).

Other ongoing first-line phase III checkpoint blockade combination trials in NSCLC include the CheckMate-227 study, which is comparing platinum-based doublet chemotherapy with nivolumab (Opdivo) monotherapy, the combination of nivolumab and ipilimumab (Yervoy), and the combination of nivolumab and platinum-based chemotherapy (NCT02477826).

In the IMpower130 study, the combination of atezolizumab (Tecentriq) plus nab-paclitaxel and carboplatin is being compared with the chemotherapy doublet in 724 chemotherapy-naïve patients with stage IV nonsquamous NSCLC (NCT02367781).

The phase III MYSTIC trial is evaluating the combination of the PD-L1 inhibitor durvalumab (Imfinzi) with the CTLA-4 inhibitor tremelimumab. In January, the primary endpoint was adapted to include OS in addition to PFS. At this time, the MYSTIC trial is no longer recruiting new participants (NCT02453282).

Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.

2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. 

Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. 

 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.

Less than 2 years after checkpoint blockade immunotherapy first became available for patients with non-small cell lung cancer, the PD-1 inhibitor pembrolizumab is poised to reshape the treatment paradigm for previously untreated individuals without molecular mutations. 

Immunotherapy Gains Frontline Foothold in NSCLC

The B-cell receptor (BCR) inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) have revolutionized the treatment of chronic lymphocytic leukemia (CLL); however, “There are still a significant number of patients who will relapse after those therapies or discontinue because they’re intolerant,” said Jeffrey Jones, MD.

At the 2016 ASH Annual Meeting, Jones presented findings from a phase II study demonstrating high response rates with the BCL-2 inhibitor venetoclax (Venclexta) among patients with CLL who had progressed, relapsed, or were refractory to ibrutinib (n = 43), idelalisib (n = 21), or both agents (n = 4). The overall response rate with venetoclax was 67%, including 70% of patients previously treated with ibrutinib and 62% treated with idelalisib.

: Can you discuss the design of the study?

 at ASH, Jones, an assistant professor of Internal Medicine in the Division of Hematology at The Ohio State University, discussed the promising early data for venetoclax in CLL after progression on BCR-pathway inhibitors, as well as the next steps with the research.

: One of the things that happens in clinical medicine is new advances, no matter how great they are, often create new clinical situations and new unmet medical needs. That's happened in CLL medicine with the addition of kinase inhibitor therapy—although it is remarkably effective for the majority of patients, there are still a significant number of patients who will relapse after those therapies or discontinue because they're intolerant.

The new drug venetoclax, an oral inhibitor BCL-2, was recently approved here in the United States for treatment of CLL with deletion 17p relapsing after at least one prior therapy. That drug has a unique mechanism distinct from ibrutinib or idelalisib that makes it interesting to assess in the context of treatment failure after those drugs.

This trial was a phase II study of single-agent venetoclax in 2 parallel cohorts of patients. One was a group of patients progressing after or during treatment with ibrutinib. The second cohort of patients was progressing after or during treatment with idelalisib. In fact, the majority of patients, about 43 patients, treated in the ibrutinib arm progressed during ibrutinib treatment. On the other hand, the majority of patients treated in the idelalisib arm were treated after discontinuing ibrutinib for reasons of toxicity or tolerance. Slightly different groups of patients.

Overall, venetoclax was highly effective in both groups of patients. In the ibrutinib arm where patients had been in treatment longer, the overall response rate was 70%; it was 62% in the arm after prior treatment with idelalisib. That compares favorably with prior studies of single-agent venetoclax in relapsed/refractory CLL, many of whom had never been exposed to a kinase inhibitor.

One concern that's arisen as venetoclax is moved into the clinic is the need to better understand its toxicity profile. In some earlier studies of venetoclax, there were cases of hyperacute tumor lysis syndrome that required urgent intervention in order to manage. Modifications were made in prophylactic measures and a careful dose ramp-up schedule that was employed in the trial we're speaking about.

Is there a reason you wanted to look at venetoclax specifically?

What will the findings of this study mean for patients?

What are the next steps for this research?

With that, there were only 2 cases of biochemical tumor lysis reported in this trial between both groups of patients. Neither of those cases required urgent medical intervention like hemodialysis. The remainder of the toxicity was consistent with what had been reported in the past—chiefly hematologic, mostly neutropenia and thrombocytopenia, but not associated with a higher incidence of infection beyond what might expected in a group of relapsed and refractory CLL patients.

Retrospective data that has been presented previously and is being updated at this meeting suggests that older drugs like chemotherapy and single-agent monoclonal antibodies achieve suboptimal responses in this setting, with overall response rates no higher than 30% in patients progressing after 1 or both kinase inhibitors. Looking for drugs that have a novel mechanism of action and have a favorable safety profile is what really generates interest in general. Venetoclax is a drug like that with a distinct mechanism of action, favorable safety profile, and excellent single-agent activity, making it chief among the available drugs that are in advanced stages of clinical development. Plus, since it's an oral agent, it doesn't require hospitalization in most patients for care. There's no clinic visits for infusions. It improves patient acceptability.

As kinase inhibitors move beyond academic practice and become more widely adapted in the community, there's going to be a growing group of patients exposed to those drugs and unfortunately a larger group of patients whose disease will progress after treatment with those drugs. This is really the first prospective study in this emerging group of patients that demonstrates there is an effective option with a favorable risk benefit ration. I think this immediately suggests that the first best choice for patients, and particularly those progressing after ibrutinib who don't have access to investigational therapies, is this treatment with venetoclax.

We're presenting data on the first group of patients that was accrued to the trial. There are just over 60 patients. A larger group of patients has been treated in an expansion cohort after treatment with one or both of the kinase inhibitors. What we're really interested to understand is how durable these first responses will be. Are there some patients who are prone to early relapse? If so, can we identify who those patients are to think about other strategies for them, maybe combination strategies or early referral to transplant or CAR T-cell therapy? Among the patients who achieved durable responses, is there some indicator where the responses are sufficiently deep so they might be able to discontinue therapy in the future?

Overall, many people are interested in thinking about these drugs given concurrently rather than sequentially, as was done in this trial. Is there a way of giving ibrutinib with venetoclax as a way of preventing the clinical situation we're describing, which is a high-risk patient with disease progressing because of acquired resistance [to one of those drugs]? Many of our great successes in oncology have come with combination therapies using drugs with nonoverlapping mechanisms of action and nonoverlapping toxicity profiles. That's the next step as we move forward with the novel targeted agents.

Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 637.

Jeffrey Jones, MD, discusses promising early data for venetoclax in chronic lymphocytic leukemia after progression on BCR-pathway inhibitors, as well as the next steps with the research.

Expert Discusses Value of Venetoclax After BCR Inhibition in CLL

Silas Inman, Senior Vice President, Content, joined MJH Life Sciences™ in early 2011 as one of the company's first web editors. In this position, he built OncLive.com from a fledgling web platform to a leading source of oncology news for community oncologists via in-depth reporting of breaking news from major medical conferences and the launch of OncLive® TV. 

Throughout his tenure at MJH, Silas has been accountable for several organic launches of highly successful brands, including Targeted Oncology™ and NeurologyLive®, and for quickly transforming acquisitions into high-functioning business units. Prior to joining MJH, Silas, who attended Eastern Michigan University, was an EMT, frontend web developer, and social media/SEO expert. Follow him on Twitter 

ASCO named the vastly improved outlook for patients with chronic lymphocytic leukemia (CLL) as its inaugural “Cancer Advance of the Year.” Specifically, the organization is recognizing the approval of four new therapeutic options for CLL over 2013/2014: obinutuzumab, ibrutinib, ofatumumab, and idelalisib.

The announcement was made as part of ASCO’s release today of its annual update on oncology treatment advances: 

Clinical Cancer Advances 2015: ASCO's Annual Report on Progress Against Cancer

“These new therapies fill an enormous need for thousands of patients living with CLL,” said Gregory Masters, MD, ASCO expert and co-executive editor of the report, in a statement. “For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle.”

The immunotherapies obinutuzumab (Gazyva) and ofatumumab (Arzerra) are approved in the frontline CLL setting, while the small-molecule inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) are approved for resistant/relapsed CLL.

The first of these four agents approved over 2013/2014 was the anti-CD20 agent obinutuzumab. In November 2013, the FDA approved the drug in combination with chlorambucil as a first-line treatment regimen for patients with CLL based on data from the phase III CLL11 trial. In the study, the obinutuzumab/chlorambucil combination significantly reduced the risk of progression by 84%, when compared with chlorambucil alone. 

The approval came with a Boxed Warning, similar to other monoclonal antibodies in this class, regarding hepatitis B reactivation and progressive multifocal leukoencephalopathy, a rare disorder affecting the brain.

In December 2014, the FDA updated the label for obinutuzumab plus chlorambucil to include data from stage 2 of the CLL11 study, which detailed an unprecedented 11.8-month improvement in progression-free survival (PFS) compared with rituximab (Rituxan) plus chlorambucil as a frontline treatment for patients with CLL (26.7 months  vs 14.9 months; HR = 0.42; 95% CI, 0.33-0.54; 

The next new option approved for patients with CLL was the BTK inhibitor ibrutinib in February 2014. The FDA approved the agent for patients with CLL who have received at least one previous therapy. The decision was based on data from 48 patients enrolled in the single-arm phase Ib/II PCYC-1102-CA study. At a median 15.6-month follow-up for this group, single-agent ibrutinib produced an overall response rate (ORR) of 58.3% (all partial responses) with a duration of response of up to 24.2 months.

The most common grade 3/4 nonhematological adverse reactions were pneumonia (8%), hypertension (8%), dehydration (6.4%), atrial fibrillation (6.3%), and sinusitis (6%). Additionally, ibrutinib-related grade 3/4 cytopenias were reported in 35% of patients.

In July 2014, the FDA expanded the approval of ibrutinib to include the treatment of patients with CLL who harbor a 17p deletion, based on findings from the phase III RESONATE trial. In RESONATE, ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab.

The anti-CD20 agent ofatumumab, which received a new indication in April 2014, marked the third new CLL treatment option made available over 2013/2014. The indication is for ofatumumab plus chlorambucil for previously untreated patients with CLL who are considered inappropriate for treatment with the chemotherapy fludarabine. The FDA first approved ofatumumab in October 2009 for the treatment of patients with CLL who no longer respond to chemotherapy.

The new approval was based on results from the phase III COMPLEMENT 1 trial, in which ofatumumab and chlorambucil demonstrated a 9.3-month improvement in PFS compared with chlorambucil alone. The ORR with the combination was 82% versus 69% with chlorambucil alone.

Grade 3/4 adverse events occurred in 50% of patients treated with ofatumumab compared with 43% in the chlorambucil monotherapy arm. The most common grade 3/4 toxicity was neutropenia, which occurred in 26% of patients treated with ofatumumab compared with 14% for chlorambucil alone. Grade 3/4 infusion-related adverse events were reported in 10% of patients treated with ofatumumab compared with none for those receiving chlorambucil alone.

And rounding out the impressive 2013/2014 breakthroughs in CLL care was the July 2014 approval of the PI3K-delta inhibitor idelalisib in combination with rituximab for patients with high-risk relapsed or refractory CLL. The approval was based on the phase III Study 116 trial, in which the addition of idelalisib to rituximab improved overall survival by 72% and PFS by 82% versus placebo and rituximab.

	The approval for idelalisib included a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation associated with idelalisib. To address concerns with these side effects, idelalisib was also approved along with a Risk Evaluation and Mitigation Strategy (REMS).

	In a statement on the naming of these CLL breakthroughs as the Cancer Advance of the Year, ASCO President Peter P. Yu, MD, said, “This has truly been a banner year for CLL and for clinical cancer research as a whole. Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients.”

, now in its 10th year, was published online today in the 

. The 2015 report was developed by an editorial board of 18 experts representing a wide spectrum of oncology specialties.

	Beyond announcing the top advancement in cancer, this year’s report also includes a look back at the last 10 years in oncology and a look forward at projected trends for the next decade, as well as sections on the top research advances from the past year and promising early advances in rare cancers.

ASCO named the vastly improved outlook for patients with chronic lymphocytic leukemia as its inaugural "Cancer Advance of the Year." 


ASCO Selects Dramatic Improvement in CLL Care  as 'Cancer Advance of the Year'

As the Avastin (bevacizumab) drama continues at the FDA, the National Comprehensive Cancer Network (NCCN) has weighed in. The NCCN’s 2011 Guidelines for Breast Cancer continue to recommend Avastin in metastatic breast cancer, despite the FDA’s move toward revoking the indication. Addressing another hot-button oncology issue, the updated guidelines do not recommend routine CYP2D6 testing prior to tamoxifen treatment. The 2011 guideline updates were presented at the NCCN 16th Annual Conference, which took place from March 9-13 in Hollywood, Florida.

In February 2008, Avastin received accelerated approval for the treatment of HER2-positive metastatic breast cancer, based on clinical trial data showing it improved progression-free survival (PFS) by 5.5 months. Full approval was contingent on follow-up trials further supporting Avastin’s efficacy and safety; however, the PFS advantage in 2 major follow-up studies—while still positive&mdash;was far lower than what was reported in the original trials, and there was no overall survival benefit. Avastin was also associated with increased toxicity. The FDA’s Oncologic Drugs Advisory Committee subsequently voted 12 to 1 in July 2010 to revoke Avastin’s breast cancer indication.

As the agency moves toward enacting the panel’s recommendation, it has granted Avastin manufacturer Genentech a hearing on June 28 and 29. Genentech’s major argument against revocation will likely be that even though the follow-up trials underperformed and demonstrated no survival benefit, Avastin still improved PFS in some women with metastatic breast cancer.

The NCCN used similar logic in maintaining its Avastin recommendation. Their 2011 Guidelines for Breast Cancer continue to support Avastin use, based on the PFS benefit demonstrated in the major Avastin trials.

Various clinical studies have identified the enzyme CYP2D6 as a potential biomarker for tamoxifen efficacy in patients with early-stage, endocrine-responsive breast cancer; however, 2 major retrospective studies have placed severe doubt on the prognostic value of CYP2D6.

Subanalyses of the Breast International Group (BIG) 1-98 and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trials found no association between CYP2D6 status and breast cancer—free survival in patients treated with tamoxifen. Based on the entirety of available data, the 2011 NCCN Guidelines for Breast Cancer do not recommend standard CYP2D6 genotyping in evaluating treatment with tamoxifen.

The complete NCCN Guidelines for breast and other cancers are available at 

As the Avastin (bevacizumab) drama continues at the FDA, the National Comprehensive Cancer Network (NCCN) has weighed in.

NCCN 2011 Guidelines for Breast Cancer: Yes on Avastin, No on CYP2D6

	PC users, is the impending April 3 iPad release giving you tablet envy? Well, rest assured: Coinciding with the iPad’s arrival, 

(HP) expects to release the HP EliteBook 2740p, an ultra-thin, multi-touch—enabled, convertible tablet optimum for business and healthcare professionals on the go. The EliteBook 2740p (starting at $1599) combines the full functional capability of an HP notebook PC with the unrestrained flexibility of a tablet. The hybrid device easily transforms from a notebook to a tablet through the simple manipulation of a convertible hinge. Starting at 3.8 pounds, the 2-in-1 EliteBook 2740p is easily transported, allowing you to remain productive in any situation. It comes standard with a 12.1-inch diagonal LED display, with the option to purchase a screen that enhances viewing in natural light. Users can operate the tablet with an included stylus or the touch screen, which allows swift navigation via simple finger taps and screen swipes. The device comes loaded with HP software, including HP QuickWeb, which enables Web access when the computer is shut down, and a trial version of HP SkyRoom, which allows high-

	definition videoconferencing. An HP 2740 Ultra-Slim Expansion Base (starting at $299) can be purchased to dock the PC for use with peripherals.

	Tired of always relying on a crowded, distraction-filled Starbucks as your WiFi hotspot? Using the mobile network, Connect

 allows you to create your own personal hotspot wherever and whenever you want. Wi-REACH

, which retails for $99, is ideal for healthcare professionals who frequently travel. The small, plastic device resembles a battery charger and allows you to use your existing 3G USB dongle (a mobile broadband modem that provides Internet access via 3G signaling). The

	dongle easily connects and slips inside the top of the Wi-REACH

. You can also purchase a model that comes with an embedded 3G dongle. Once you are set up, the push of a button connects your WiFi-enabled device to Wi-REACH

 via WiFi, and then to the Internet through the mobile network. It requires no installation or client software and the wireless links are secure. Each Wi-REACH

 allows you to simultaneously use up to 10 devices through password-protected connections. The standalone Wi-REACH

 runs on a rechargeable battery that lasts several hours.

 Wireless Keyboard is a handheld mini keyboard that allows multimedia wireless control in any working environment. Oncologists and other healthcare professionals may find the Rii Mini useful for conferences, presentations, and lecturing. The device has a full QWERTY keyboard with 69 keys, an integrated touchpad that works horizontally and vertically, and a laser pointer. The portable unit measures 151 mm x 59 mm x 13 mm, weighs 103 g, can operate from a 30-meter range, and connects to the device of your choice via a 2.4-GHz USB receiver. Twenty-six bright LED lights backlight the Rii Mini for use in darker environments. Its built-in, rechargeable, lithium-ion battery should last for 1 month. The Rii Mini also facilitates PC multimedia entertainment, as home theater PC users can relax on their couch and use the Rii Mini as easily as their TV remote control. The device retails for $92 and comes with a USB receiver and USB cable. For additional product analysis, be sure to check out the 7.5-minute 

Oncology Gadget Watch: April 27, 2010

	A US district court invalidated 7 of 23 of Myriad Genetics, Inc’s patents on the 

 genes, which confer an increased risk of developing breast, ovarian, and prostate cancers. If upheld, the decision by Judge Robert W. Sweet would threaten existing patents on thousands of genes and curtail the rights of an individual or organization to patent a gene. Biotechnology industry analysts predict that prohibiting gene patenting will stall advances in genetic research by diminishing financial incentives. Several research professionals disagree and believe restricting gene patenting expands genetic research opportunities.

	The Association for Molecular Pathology, the American Civil Liberties Union (ACLU), and the Public Patent Foundation filed the lawsuit against the US Patent and Trademark Office and Myriad last year. They argued that the patents limit patient access to affordable, high quality testing for cancer-causing 

mutations. Myriad manufactures the only test available in the United States to detect the patented 

mutations, and each analysis costs more than $3000. Its patents make it virtually impossible for another company to develop a diagnostic test for the cancer-causing mutations. The plaintiffs’ other complaint is that the gene patents stymie progress in finding cures for cancer because Myriad restricts researchers’ access to the genes, and there is no workaround when investigating 

	Sweet agreed with the plaintiffs’ primary argument—that genes are products of nature and cannot be patented. Myriad countered that because the genes had been isolated from the DNA, they were no longer in their natural state. The judge disagreed and said the genetic sequences did not meet the Supreme Court precedent of having “markedly different characteristics” from their natural state, nor did they possess a “new or distinctive, form, quality, or property.” He compared it to a case in which the court ruled that refined cellulose&mdash;purified pulp obtained from wood or vegetable matter&mdash;could not be patented because, while the process to obtain it might be “the creature of invention,” the extracted material was still cellulose, a naturally occurring substance. While the Supreme Court has held that genetically altered microorganisms can be patented, Sweet said this is because these microorganisms do not occur in nature. In summary, Sweet concluded that isolated DNA differs little from non-isolated DNA because it leaves the nucleotide sequence intact and is therefore a discovery, not an invention.

	Some of the contested patents gave Myriad the exclusive right to analyze 

nucleotide sequences for mutations or compare them against a reference sequence. Another patent prohibited anyone from assessing the growth rate of recombinant cells containing the 

genes in response to therapeutic treatments. Sweet said none of these process patents were valid because the methods involved an abstract mental process that did not involve transforming the genetic material in any way.

	Sweet’s decision surprised intellectual property law experts. The US Patent and Trademark Office has been granting gene patents for years, and they expected the judge to dismiss the lawsuit. Some expect portions of Sweet’s ruling to be overturned on appeal. Myriad has already indicated it will appeal the decision to the 2

 US Circuit Court of Appeals in Manhattan. Given the significant ramifications of the findings on the field of research and diagnostics, either party will undoubtedly appeal to the Supreme Court in the event of an adverse ruling.

	The National Institutes of Health estimates that nearly 20% of the human genome has been patented, with many of the genes linked to diseases like Alzheimer’s, cancer, and muscular dystrophy. Universities hold some of these patents, whereas others are held by diagnostic and biotechnology companies. In some cases, the discovery of a gene becomes the foundation for a new venture. This was the case with Myriad; Mark Skolnick, the University of Utah researcher who discovered the gene, went on to found the company.

	Critics of gene patents have long maintained the patents create corporate monopolies that restrict genetic research and eliminate open competition that could yield better and cheaper tests. They view the ruling as a major breakthrough, and believe the decision will transform the established paradigm governing the field of genetic testing if it is not overturned. ACLU staff lawyer Chris Hansen, who helped argue the case, said, “The human genome, like the structure of blood, air or water, was discovered, not created. There is an endless amount of information on genes that begs for further discovery, and gene patents put up unacceptable barriers to the free exchange of ideas.”

	In a statement on the ACLU’s Website, Selene Kaye of the ACLU’s Women’s Rights Project called the decision “a huge victory for women’s health and scientific freedom.” She cautioned that the fight was not over, however. Myriad points to the large number of studies involving 

genes as proof that its patents have not stifled research. The company said that, in addition to making the information available for research, it publicizes data from its own research involving the genes. “We are very confident that the Court of Appeals for the Federal Circuit will reverse this decision and uphold the patent claims being challenged in this litigation,” Peter Meldrum, Myriad’s president and CEO, said in a statement.

A US district court invalidated 7 of 23 of Myriad Genetics, Inc's patents on the BRCA1 and BRCA2 genes, which confer an increased risk of developing breast, ovarian, and prostate cancers.

Jason Broderick