The OBR Blog

November 22, 2016 - 03:11 am comments0 Comments

This year’s ASH Annual Meeting will be chock-full of interesting, informative, and clinically useful presentations, according to a whirlwind tour of highlights presented at a pre-meeting Webinar by ASH President Charles Abrams, MD, and Stephanie Lee, MD, ASH Secretary.

Starting with the most immediately clinically applicable studies, Dr. Lee singled out two studies of approved agents in narrow disease states: Abstract 182 and 145.

Abstract 182 provides results of the Phase 3 ALCANZA trial comparing brentuximab versus physician’s choice of therapy (methotrexate or bexarotene) in CD30-expressing cutaneous T-cell lymphoma (CTCL), a relatively rare disease. The study included 128 randomized patients followed for 17.5 months. For the primary endpoint, overall response rate (ORR) at 4 months, brentuximab was significantly superior to physician’s choice of therapy: 56% versus 13%, respectively (P<.0001). Median progression-free survival (PFS) was 16.7 months versus 3.5 months, a highly significant difference favoring brentuximab (P<.0001).

“This study showed that brentuximab has a significant advantage over the other two options used to treat CTCL,” Dr. Lee told listeners.

Abstract 145 presents final results of the Phase 3 LyMa trial that compared rituximab maintenance every 2 months for 3 years versus observation in younger patients with mantle cell lymphoma (MCL) in response after undergoing autologous stem cell transplant (ASCT). The study included 240 patients with a median follow-up of 50 months. Four-year event-free survival (EFS) was 78.9% for rituximab maintenance versus 61.4% for observation (P=.0012). Four -year progression-free survival (PFS) and overall survival (OS) were also improved with rituximab maintenance therapy. Four-year PFS was 8.2.% versus 64.6%, respectively (P=.0005), and 4-year OS was 88.7% versus 81.4%, respectively (P=.0413).

“This study provides good evidence that rituximab improves outcomes after ASCT in younger patients with mantle cell lymphoma. Some hematologists are already doing this, and now there is evidence [to support this practice] from a Phase 3 trial,” Dr. Lee noted.

Abstract 6 showed a 34% reduction in risk of progression or death with obinutuzumab versus rituximab as induction and maintenance therapy in about 1200 patients with previously untreated follicular lymphoma with Stage 3 or 4 or bulky Stage 3 disease, according to primary results of the Phase 3 GALLIUM trial.. Patients were randomized 1:1 to obinutuzumab versus rituximab (both anti CD20 agents) at induction. No difference in complete response or partial response was observed after induction therapy. Patients continued on maintenance therapy for 2 years. More Grades 3 and 5 severe adverse events occurred with obinutuzumab.

“These data show that obinutuzumab is more effective in prolonging time to relapse, but the caveat is greater toxicity,” Dr. Lee commented.

CAR-T THERAPY

Dr. Abrams highlighted two studies using genetically engineered chimeric antigen receptor (CAR) T cells. A late-breaker (Abstract LBA 6) showed that Kte-CD19 CAR T cells induced responses in 76% of 101 patients from 22 institutions with refractory diffuse large B-cell lymphoma in the pivotal Phase 2 ZUMA-1 trial. ORR was 76% (47% complete response [CR] rate and 29% partial response rate [PR]). PFS was 56% at 3 months, which Dr. Abrams called “impressive.”

“The T-cells were engineered within 17 days from apheresis, which is a relatively quick turnaround. This treatment is not for the faint of heart, but it does induce complete remissions in some patients. This novel technology can be extended to many centers in the community, even those with no experience using CAR T,” Dr. Abrams noted.

A second study (Abstract 650) found that anti-CD22 CAR T cells had encouraging results in a small study of 9 “tough to treat” patients (children and young adults) with relapsed/refractory acute lymphoblastic leukemia (ALL). All 9 patients had at least 1 prior transplant, and 2 had undergone 2 prior transplants. Patients had chemotherapy and then were given anti-CD22 CAR T. Interim results at 1 month showed that 4 of the 9 patients had CR with no evidence of minimal residual disease.

“This approach with CAR T is a little different, aimed at a different target of T cells with CD 22 expression. This is encouraging, suggesting that the target of CAR T can be expanded. Someday we may be using a panel of targets,” Dr. Abrams commented.

OTHER HEMATOLOGIC MALIGNANCIES

Patients with high-risk chronic lymphocytic leukemia (CLL) were randomized 2:1 to lenalidomide maintenance versus placebo after front-line chemotherapy in the randomized, controlled, German CLLM1 trial (Abstract 229). Interim analysis of the first 89 patients of a planned enrollment of 200 showed such robust results for lenalidomide, that the trial was stopped early. At a median follow-up of 17.7 months, PFS was not yet reached in the lenalidomide-treated group versus 14.6 months for placebo. Patients treated with lenalidomide were 80% more likely to be converted to node-negative disease compared with placebo. No difference in OS was observed between the two groups with short follow-up.

“These interim findings suggest that lenalidomide maintenance is beneficial in high-risk CLL. We need continued follow-up of these patients,” Dr. Lee commented.

Although the investigational drug pacritinib was found effective in myelofibrosis in a Phase 3 trial (Abstract LBA 5), development of the drug was put on hold by the FDA due to potential cardiovascular excess deaths and hemorrhagic events in the PERSIST-1 trial. The Phase 3 PERSIST-2 study evaluated pacritinib versus best available therapy (including the JAK inhibitor ruloxitinib in 44%) in 311 patients with myelofibrosis and platelet counts <100,000 µ/l. Patients were randomized 1:1 to pacritinib versus best available therapy. Pacritinib was superior, with a 35% reduction in spleen volume, and significantly more improvement in time to symptoms at 24 weeks. Although some gastrointestinal and hematologic toxicities were observed with pacritinib, no difference between the two treatment arms was seen in cardiovascular events and bleeding.

PERSIST-2 is the only randomized trial to date in patients with myelofibrosis and thrombocytopenia and prior JAK2 inhibitor exposure. “This study is intriguing. Pacritinib did improve symptoms and spleen volume, but it remains to be seen what the FDA will do,” Dr. Lee said.

Another late-breaking abstract (LBA 1) was based on the randomized, controlled, Phase 3 StaMINA trial, which compared three different approaches to multiple myeloma in transplant-eligible patients using upfront autologous hematologic cell transplant (auto HCT): auto HCT plus RVD (bortezomib, lenalidomide, dexamethasone); tandem auto HCT plus lenalidomide maintenance (TAM); and auto HCT with lenalidomide maintenance (AM). The study enrolled 758 patients. At 38 months, PFS and OS were similar in all three groups. The probability of PFS was 57%, 56%, and 52% for the three approaches, respectively; the probability of OS was 86%, 82%, and 83%, respectively.

This is the largest randomized U.S. transplant trial in myeloma. “Results of StaMINA suggest that the addition of more chemotherapy or more transplant does not improve outcomes. All of these are reasonable approaches,” Dr. Lee noted.

SESSION ON QUALITY

Turning to a different area, Dr. Lee cited a Special Symposium on Quality of Care in the Era of Health Improvement Technology. Three different speakers will tackle the question of whether the new technology is having an impact on patient care.

“I hope this symposium will dig into the current experience for patients and for researchers,” she said.

“There is something for everyone at the upcoming ASH meeting,” she noted.

 

November 21, 2016 - 06:11 pm comments0 Comments

By: Deni Deasy Boekell, Senior Director, Commercial Strategies & Market Access, Kantar Health

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Market forces continue to drive oncology practices to align, invest and adapt to capture patient volume, adjust to decreasing payer reimbursement, optimize revenue, and reduce financial risk.

Affiliation with or even acquisition by an integrated delivery network (IDN) is an attractive option for many practices, offering access to increased patient volume, higher reimbursement through the institution, protection from carrying costs and patient cost-share risk, reduced administrative burden, and inclusion in payment models moving toward integrated patient care.

According to our survey of 150 independent community-based and 80 hospital-owned or -affiliated oncology practices, 35% of independent community oncology practices engaged in some form of business association within the past two years; the majority were affiliations with a hospital/IDN. In addition 22% of oncology practices are considering affiliation with an IDN in the next 24 months.

This means more and more cancer patients are receiving their care through an IDN-affiliated or -owned practice, and those practices are leading investment in capabilities, reimbursement and business models. This shift in oncology care through IDNs is affecting patient treatment in three ways: increasingly centralized management of oncology, focus on cost effectiveness catalyzed by novel reimbursement, and adaptations to increased patient involvement in care planning.

1. IDN centralized management of affiliated oncology practices

Centralized management is being implemented through increasing CPOE/decision support tools to help select drugs, the use of pathways with management controls (e.g., step requirements), and centralized drug acquisition and/or formulary. More than 80% of IDN practice respondents reported being subject to IDN mechanisms that affect prescribing.

IDNs most often use decision support tools, centralized drug formularies and pathways to direct oncologists toward preferred therapies. Pathways are a key mechanism by which IDNs may influence oncologists’ treatment decisions, and IDN oncologists are more likely to be exposed to pathways than are their independent community practice colleagues.

2. Increasing focus on cost effectiveness catalyzed by novel reimbursement

Almost half (46%) of IDN oncologists reported participating in an accountable care organization (ACO) in 2016 (up from 40% in 2015), affecting one-third of their patients on average. ACO-participating IDN practices are more likely to focus on cost-effective treatments, reduction in redundant care, and the quality of life for their ACO patients.

3. Adaptation to increased patient involvement in care planning

While IDN practices most often direct patients with cost concerns to financial support, they do so less frequently than independent community practices. The IDN oncologists are also increasingly looking to less costly drug alternatives in response to affordability issues.

Of note, the 26% response indicating use of less costly drug options in the IDN is up from 13% in 2015.

IDN oncologists are more likely to have end-of-life planning discussions with patients (frequently triggered by changes in patient status) and to have these discussions result in reductions in the use of therapeutic options for most of these patients.

IDNs are structurally different from community practices, and these differences are influencing traditional cancer care delivery and decision making. Given the growing importance of IDNs in oncology care, it’s important to understand how this shift will change cancer care delivery and patient care.

October 25, 2016 - 05:10 pm Posted in Uncategorized comments0 Comments

I have extensive experience in “real world” policy-setting and decision-making and I am puzzled about the motivations regarding the attempt to transfer and recast the failed Quality Adjusted Life Years-based NICE program in the UK to the USA. Among other things, this concern is based upon the findings (Oct. 2014) of the EchOutcome Committee appointed by the European Commission whose chairman concluded that:

“The research provides robust scientific evidence that Quality Adjusted Life Years produce hugely inconsistent, wrong results on which important decisions are being made.”

I add that it has been noted that these wrong NICE-driven decisions have been correlated with decreases in OS across tumor types driving the UK to the “Bottom of the Barrel” in terms of OS across many tumor types compared to other developed Western European countries. Why do we want such a life-threatening process to be transposed to the US by ICER?

Further I note the points (OBR Green on Oct.19) made by 5 eminent Key Opinion Leaders who treat lung cancer every day.

“For us as practicing oncologists and lung cancer researchers, this report has raised serious concerns regarding ICER’s ability to interpret clinical evidence and reach conclusions on drug value that are scientific, comprehensive, and unbiased. ICER appears to represent a perspective that is less oriented toward patient benefit than toward motivations that would limit patient access to new therapeutic options. ICER’s clinic-economic methods include approaches and metrics that, due to their singular focus on population level health, would likely fail patients on an individual clinical needs basis!”

In looking at the roster (Drs. Ettinger, Schwartzberg, Otterson, Jahanzeb, Waterhouse) of experts, I am in full agreement with them. Further, I see many more points that bear extensive examination and discussion. These points include:

  • Across Value Metric Frameworks, including ICER, the failure to use or at least recognize the “Real Price” (e.g., minus 340B and Medicaid discounts) leaves an important piece out of the ICER analysis.
  • Making comparisons and valuations across disparate patient populations (e.g., PD-L1 expression levels) leads to almost absurdly different and misleading comparative values.

Finally, and most importantly, here is a critical lesson that I learned at Aetna making real world decisions daily that directly impacted the lives of 15 million people and that should be duly noted.

“Those who engage in the development of assessments of Evaluation and Valuation must be willing to live with, in an ABSOLUTE manner, (e.g., no appeals, no nothing) the decisions based upon their own assessments realizing that someday such assessments (e.g., ICER) may drive and direct decisions about the treatment of their mother, sister, brother, spouse, children etc.”

by William McGivney, PhD, Managing Principal for McGivney Global Advisors, and former long-time CEO of the NCCN, VP for Clinical and Coverage Policy at Aetna, and Member of the Medicare Coverage Advisory Committee

October 10, 2016 - 02:10 pm Posted in Uncategorized comments0 Comments

By Emily Benesh, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

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Faslodex® (fulvestrant, AstraZeneca) was approved in 2002 for the treatment of postmenopausal metastatic hormone receptor (HR)-positive breast cancer patients following prior anti-estrogen therapy. To date, utilization of Faslodex has favored second- and third-line settings for this indication, while aromatase inhibitors (AI) are generally favored in the first line for postmenopausal patients. Unlike AIs, which inhibit estrogen biosynthesis, Faslodex is an estrogen receptor antagonist (a selective estrogen receptor degrader (SERD)) that competes with estrogen to bind to estrogen receptors.  Since Faslodex acts through a different mechanism than AIs, it may represent an attractive treatment option in the first line for physicians concerned about bone loss caused by AIs. AstraZeneca previously marketed the AI Arimidex® (anastrozole), but since it lost patent protection in 2010 AstraZeneca has been looking to reestablish a branded agent (Faslodex) in the first-line postmenopausal setting. Indeed, AstraZeneca supported the FIRST trial, an open-label randomized Phase II study that evaluated Faslodex (500 mg) versus anastrozole (1 mg) as first-line hormone therapy in 205 women with postmenopausal HR-positive, locally advanced or metastatic breast cancer; notably, 72% and 78% of patients in each arm, respectively, have received no prior endocrine therapy. Faslodex was superior to anastrozole in both time to progression (23.4 versus 13.1 months; HR: 0.66, P=0.01) and overall survival (54.1 versus 48.4 months; HR: 0.70, P=0.04),1,2 prompting further evaluation of Faslodex in the first-line setting.

The objective of the Phase III FALCON trial was to confirm the superiority of Faslodex over anastrozole in postmenopausal HR-positive and HER2-negative patients with locally advanced/metastatic breast cancer who had not received prior endocrine therapy. FALCON was a double-blinded international trial that randomized patients to either Faslodex (500 mg subcutaneous injection on Day 0, 14 and 28, then every 28 days) or anastrozole (1 mg oral once daily).  The primary endpoint was progression-free survival (PFS), with several secondary endpoints including overall survival and objective response rate. Patients were included had WHO performance status of 2 or better and greater than one measurable or non-measurable lesion. Exclusionary criteria included prior endocrine therapy, systemic estrogen-containing hormone-replacement therapy use six months or less prior to randomization, presence of life-threatening metastatic visceral disease, and prior systemic treatment except one line of chemotherapy or radiotherapy.

AstraZeneca announced via press release in May 2016 that FALCON met its primary endpoint, but the data outcomes remained unknown until presented today at the 2016 European Society of Medical Oncology (ESMO) conference.3 Median PFS was improved by 2.8 months in favor of Faslodex (16.6 months for Faslodex versus 13.8 months for anastrozole; HR: 0.797, p = 0.0486). Overall survival was not significantly different between the arms (HR: 0.88, P=0.428), although the study had reached just 31% maturity. No significant differences were found in overall response rate, clinical benefit rate, or median time to deterioration by FACT-B total score. Immature duration of response endpoints showed promise (20.0 versus 13.2 months, Faslodex and anastrozole, respectively) as did duration of clinical benefit (22.1 versus 19.1 months, Faslodex and anastrozole, respectively); although statistical significance was not reported for these endpoints, the authors noted that they were trending toward significance. Overall safety profiles were generally similar between the two arms, with modestly higher signals in the Faslodex arm for arthralgia (16.7% versus 10.3%), myalgia (7.0% versus 3.4%), and ALT increase (7.0% versus 3.0%).

Interestingly, subgroup analysis found that PFS more strongly favored the Faslodex arm in patients lacking visceral metastatic disease. In the subpopulation of 208 patients, only 53.7% had a progressive event in the Faslodex arm, compared with 69.9% of patients in the anastrozole arm (22.3 months versus 13.8 months median PFS, respectively; HR: 0.592). No difference was observed in PFS between the Faslodex and anastrozole arms in patients with visceral metastatic disease. The generalizability of these findings was strengthened by similar PFS improvements in the Faslodex arms of the FIRST1,2 and CONFIRM4,5 trials.

Despite the fact that the FALCON trial met its primary endpoint, Faslodex will have hurdles to overcome in order to gain utilization in the front-line setting for this patient population. The largest hurdle faced by Faslodex in the first line is competition with the CDK 4/6 inhibitors. Ibrance® (palbociclib, Pfizer) is already U.S. FDA-approved in combination with letrozole in the first-line setting and in combination with Faslodex in AI-pretreated metastatic breast cancer, and a European approval is currently pending. Given the exemplary data that Ibrance/letrozole demonstrated in first line in comparison to letrozole alone (PFS: 24.8 versus 14.5 months, respectively, HR=0.58, p<0.000001)6, the 2.8-month benefit for Faslodex demonstrated in the FALCON trial in a very selective group of hormone-naïve first-line patients is not expected to unseat current use of the Ibrance/letrozole combination. Where Faslodex may find use in first-line is in those patients who don’t currently receive an Ibrance combination. Metastatic breast cancer patients with very indolent disease that has demonstrated strong sensitivity to endocrine therapy may be treated with a single agent hormone therapy upon first metastatic recurrence; the superiority that Faslodex demonstrated over anastrozole may support its use in first-line in some of these patients. However, that displacement may not be widespread given the small degree of benefit (2.8 months median PFS, PFS HR 0.797, and no overall survival benefit). Where Faslodex may find a niche role in first-line is in patients with bone-only disease (non-visceral), patients at risk for bone complications, or in patients who are not compliant with oral therapies.

The FALCON results suggest that for the vast majority of metastatic breast cancer patients, Faslodex will continue to play a strong role in the second- or third-line settings. Several Phase III trials in the relapsed setting that have combined Faslodex with targeted agents are underway, and indeed the Phase III PALOMA-3 trial has already reported impressive results for the combination of Faslodex plus Ibrance in AI-pretreated patients.7 Knowing that Ibrance plus Faslodex is superior to Faslodex alone in the second-line setting, there has been speculation that positive results in FALCON could spur use of this combination in the first-line setting. However, the small magnitude of benefit actually observed in FALCON will likely limit use of this combination in first-line in clinical practice.

The positive results from the FALCON trial will be viewed as an important advance for a select group of metastatic breast cancer patients (HR-positive, HER2-negative and endocrine therapy-naïve). While the FALCON results will allow Faslodex to take flight into first-line for this niche patient group, ultimately this bird of prey can’t out-compete a bird of peace8

References:

  1. Robertson JF, Lindemann JP, Llombart-Cussac A, et al., “Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study,” Breast Cancer Res Treat, 136(2): 503-11, 2012.
  2. Robertson JF, Llombart-Cussac A, Felti D et al., “Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the Phase II ‘FIRST’ study,” Abstract S6-04, SABCS, 2014.
  3. Ellis MJ, Bondarenko IM, Trishkina E, et al.; “FALCON: A phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer;” Annals Oncol, 27 (s1):  Abstract LBA 14_PR, 2016.
  4. Di Leo A, Jerusalem G, Petruzelka, et al.; “Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer;” J Clin Oncol, 28 (30): 4548-4550, 2010.
  5. Di Leo A, Jerusalem G, Petruzelka L, et al., ” Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial,” J Natl Cancer Inst, 106 (1): djt337, 2013.
  6. Finn RS, Martin M, Rugo HS, et al.; “PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC);” J Clin Oncol 34, 2016 (suppl; abstr 507).
  7. Turner NC, Ro J, Andre F, et al.; “Palbociclib in Hormone-Receptor–PositiveAdvanced Breast Cancer;” New  Engl J Med,  2015, DOI: 10.1056/NEJMoa1505270.
  8. PALOMA is derived from Latin “palumbus” which means Dove; a symbol of Peace.

October 10, 2016 - 02:10 pm Posted in Uncategorized comments0 Comments

By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

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Tesaro’s PARP inhibitor, niraparib, has generated a lot of excitement in recent weeks. On September 12, Tesaro announced that it had received an FDA fast track designation for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer. In addition to the initiation of a rolling submission of a New Drug Application (NDA) for niraparib to the FDA that Tesaro intends to complete during the fourth quarter, the company also announced plans to submit the Marketing Authorization Application (MAA) for niraparib to the European Medicines Agency (EMA) in the fourth quarter. These plans were driven by the promise of the NOVA data that were presented today at the 2016 European Society of Medical Oncology (ESMO) meeting in Copenhagen1 and published in the New England Journal of Medicine.2 NOVA (ENGOT-OV16) was a randomized, placebo-controlled, Phase III trial conducted by the European Network for Gynecological Oncological Trial groups and investigators in the United States, Canada and Hungary. This trial compared single-agent niraparib versus placebo as maintenance therapy following second-line induction therapy in platinum-sensitive ovarian cancer patients who have either germline mutation in breast cancer susceptibility gene 1 or breast cancer susceptibility gene 2 (gBRCA) or a tumor with high-grade serous histology. One thing that sets the NOVA trial apart is the large number of patients included who do not have a gBRCA mutation (350 of the 553 total enrolled patients). The non-gBRCA mutation patients were further stratified according to tumors with homologous recombination deficiency (HRD), defined by the myChoice HRD test (Myriad Genetics).

The primary endpoint was progression free survival (PFS), which was significantly greater for niraparib compared with placebo in each of the three subpopulations (p<0.001). In the gBRCA mutant cohort, median PFS was 21.0 months in the niraparib arm (n=138) and 5.5 months in the placebo arm (n=65) (HR 0.27; 95% confidence interval [CI], 0.17 to 0.41). The same pattern was seen in the overall non-gBRCA cohort: 9.3 months with niraparib (n=234) versus 3.9 months with placebo (n=116) (HR 0.45; 95% CI, 0.34 to 0.61). Further, this effect was more pronounced in the HRD-positive subgroup of the non-gBRCA cohort: 12.9 months with niraparib (n=106) compared with 3.8 months with placebo (n=56) (HR 0.38; 95% CI, 0.24 to 0.59).

These data were received extremely positively by the crowd in attendance. During the discussion, the strong data in this “BRCA-like” group were considered particularly exciting and could change the landscape of treatment in ovarian cancer. Given the large number of non-gBRCA patients included in the trial as well as the positive results, Tesaro can seek a broad label without the BRCA mutation restriction. Indeed, during the discussion, emphasis was placed not on BRCA, or being “BRCA-like,” but rather on the platinum sensitivity of this patient population. In Europe, niraparib will be seeking a label very similar to Lynparza™ (olaparib, AstraZeneca); in the United States, however, niraparib will have a broad label, distinct from Lynparza, whose FDA-approved indication limits its use to fourth-line in patients with gBRCA mutations.

In platinum-sensitive ovarian cancer patients with gBRCA mutations, PARP inhibitors are ascendant.  As noted above, Lynparza is currently approved in the United States and Europe, albeit with divergent indications. Clovis Oncology’s rucaparib adds another dimension to this space. In a combined analysis of two Phase II studies (Study 10 and ARIEL2, n=106) and using an assay developed by Foundation Medicine, the BRCA (germ line and somatic) mutant subgroup demonstrated a 53.8% objective response rate and 10-month median PFS in patients previously treated with a median of three prior chemotherapies and predominantly platinum-sensitive.4 Previous analysis of just the ARIEL2 study indicated improved efficacy in patients with BRCA (germ line and somatic) mutation and in patients with BRCA-like HRD-positive ovarian cancer, in comparison with non-BRCA-like patients.5

The PARP inhibitors are racing to establish and gain share in this space. Clovis has completed their accelerated approval application with the U.S. FDA for use in BRCA (germ line and somatic) mutant patients who have been treated with two or more prior chemotherapies. This application received a priority review, which could put it on the market by February 2017; they plan to file an MAA in Europe by the end of 2016. Tesaro is further behind, but the robust Phase III NOVA data will likely put it at an advantage once it launches; U.S. and European filings should be complete in the fourth quarter of 2016. While Lynparza is already EMA-approved in patients with gBRCA mutations, niraparib’s Phase III data in “BRCA-like” patients may help eclipse Lynparza’s standing; in the United States, the launch of niraparib may have a more pronounced effect on Lynparza, as it is expected to be approved and utilized in an earlier treatment setting. With so many novel agents demonstrating strong efficacy, the stars are beginning to shine brightly on the ovarian cancer space.

References:

  1. Mirza MR, et al.; “A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial);” Annal Oncol, 27 (s1): Abstract LBA3_PR,2016.
  2. Mirza MR, Monk BJ, Herrstedt J, et al.; “Niraparib Maintenance Therapy in PlatinumSensitive, Recurrent Ovarian Cancer;” New Engl J Med, 2016: DOI: 10.1056/NEJMoa1611310.
  3. Kantar Health, CancerMPact® U.S. Treatment Architecture, Ovarian cancer; www.cancermpact.com; accessed October 8, 2016.
  4. Kirsteleit RS, Shapira-Frommer R, Oaknin A, et al.; “Clinical Activity of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib in Patients with High-Grade Ovarian Carcinoma and a BRCA Mutation: Analysis of Pooled Data from Study 10 (Parts 1, 2a, and 3) and ARIEL2 (Parts 1 and 2);” Annal Oncol, 27 (s1): Abstract 856O, 2016.
  5. Coleman RL, Swisher E, Oza A, et al.; “Refinement of Prespecified Cutoff for Genomic Loss of Heterozygosity (LOH) in ARIEL2 Part 1: A Phase 2 Study of Rucaparib in Patients with High-Grade Ovarian Carcinoma (HGOC);” J Clin Oncol 34, 2016 (suppl; abstr 5540).

October 10, 2016 - 02:10 pm Posted in Uncategorized comments0 Comments

By Liseth  Parra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

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A biologics license application (BLA) for Tecentriq® (atezolizumab,  Roche/Chugai) was accepted with priority review by the U.S. Food and Drug Administration (FDA)  in April 2016 for the treatment of patients with PD-L1-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) patients who have progressed on or after platinum-containing chemotherapy, an indication in which Tecentriq also has Breakthrough Therapy Designation (BTD). This filing for accelerated FDA approval was based on the single-arm Phase II BIRCH trial, in which Tecentriq produced a 17% objective response rate (ORR) in PD-L1-positive second-line NSCLC.1 Supporting data for Tecentriq in second-line NSCLC also come from the randomized Phase II POPLAR study that showed an improved median overall survival (OS) of 12.6 months with Tecentriq compared with 9.7 months with docetaxel in  second-line NSCLC (HR: 0.69, p=0.04).2  Confirmatory data to support its approval can now include the Phase III OAK trial, whose results were newly presented at the 2016 European Society of Medical Oncology (ESMO) Congress.3 A PDUFA regulatory decision for Tecentriq in second-line NSCLC treatment is expected as early as October 19, 2016.

Tecentriq is an engineered monoclonal antibody designed to block the PD-L1 protein, expressed on tumor cells and tumor-infiltrating immune cells (IC), whose main function is to inhibit T-cell immune response. Once this pathway is inactivated by a PD-L1 blocker, such as Tecentriq, the T-cell ability to attack tumor cells is restored, increasing the body’s ability to fight cancer.4 Tecentriq is one of several checkpoint inhibitors in development for NSCLC and is the first and only anti-PD-L1 cancer immunotherapy approved by the FDA to date, obtaining accelerated approval for second-line treatment of locally advanced or metastatic urothelial carcinoma (mUC) in May 2016. Genentech and Roche are aggressively developing Tecentriq in the NSCLC space, with initial commercial launch planned in the second- and third-line settings for patients who overexpress PD-L1 and with eight more Phase III trials ongoing in first-line and the adjuvant setting.

The OAK trial is a randomized, global, multicenter, open-label Phase III study, whose main objective is to evaluate the efficacy and safety of Tecentriq (1,200 mg IV, Q3W) when compared with a historical standard of care treatment, docetaxel (75 mg/m2, Q3W) in patients with locally advanced or metastatic NSCLC previously treated with platinum-containing chemotherapies. The data from OAK presented Sunday at the 2016 ESMO congress are the first Phase III results for a PD-L1 directed antibody. The trial enrolled 1,225 patients with any PD-L1 status with locally advanced or metastatic NSCLC who had one or two prior lines of chemotherapy, including at least one platinum-based. The primary and secondary endpoints for the first 850 enrolled patients were presented. Patients were randomized to receive Tecentriq (n=425) or docetaxel (n=425). Median OS was 13.8 months versus 9.6 months, respectively (HR 0.73, p=0.0003). In addition, the median OS of patients with ≥1% PD-L1 expression in immune cells (IC) or tumor cells (TC) (55%  of enrolled patients) was 15.7 months with Tecentriq versus 10.3 months with docetaxel (HR 0.74, p=0.0102). Comparable clinical significance was found in patients with IC or TC, PD-L1 expression <1%, with a median OS of 12.6 months versus 8.9 months, respectively (HR 0.75, p=0.0205). Importantly, patients with ≥ 50% TC or ≥ 10% IC PD-L1 expression (16% of enrolled patients) treated with Tecentriq had an outstanding median OS of 20.5 months compared with 8.9 months in the docetaxel treatment arm (HR: 0.41, p<0.0001). An OS benefit with Tecentriq was observed regardless of histology, although the magnitude of benefit was more pronounced in patients with non-squamous histology (15.6 versus 11.2 months; HR 0.73, p=0.0015) than in patients with squamous histology (8.9 versus 7.7 months; HR 0.77, p=0.0383). Tecentriq had a significant OS benefit across all subgroups regardless of age, PD-L1 status and smoking status, with the exception of patients harboring active EGFR mutations, who showed no benefit with Tecentriq.

Secondary endpoint results were mixed, with Tecentriq-treated patients attaining a progression-free survival (PFS) per RECIST v1.1 numerically lower than the docetaxel arm (2.8 months versus 4.0 months; HR 0.95, p=0.4928). PFS benefit increased with higher PD-L1 expression, with TC3 or IC3 subgroups presenting a median PFS of 4.2 months in Tecentriq-treated patients compared with 3.3 months in the docetaxel group. Similarly, the ORR for Tecentriq was higher in high PD-L1 expressers, with an ORR of 31% compared with 11% of patients treated with docetaxel.

In summary, the OAK study presented the first Phase III data for a PD-L1 directed antibody in lung cancer. Tecentriq will be a new option for second-line NSCLC treatment, with an adverse event (AE) profile that appears to be similar to that of other immune-checkpoint inhibitors. This is a competitive space, with Opdivo currently dominating the second-line market5 and Keytruda also approved. How will Tecentriq be welcomed given that it is coming to market one year behind its biggest rivals?

A more important question may be what role immune checkpoint inhibitors will play in second-line given the positive results of the KEYNOTE-024 trial for Keytruda in first-line PD-L1 strongly positive patients. Given those data, up to one-third of NSCLC patients (those with PD-L1 tumor proportion score of ≥ 50%) may soon receive Keytruda in the first-line setting; given the lack of data to support multiple lines of immune checkpoint inhibition, it seems likely that any patient receiving first-line Keytruda would not be considered for checkpoint inhibitor therapy in second-line, shrinking the available market considerably. Although Opdivo has a broad label in second-line, irrespective of PD-L1 expression, its negative data in the first-line CheckMate 026 trial could have a trickle-down effect on its role in second-line patients who did not receive Keytruda in first-line; this is where Tecentriq will compete with both Opdivo and Keytruda.

Overall, immuno-oncology continues to generate significant enthusiasm, with several overflow rooms set up for the large number of people who attended Sunday’s Presidential Symposium. The entrance of Tecentriq will expand the competitive set in second-line, while other presentations during this ESMO session look to the future as these immuno-oncology agents move into earlier treatment settings. And this is only the tip of the iceberg, as multiple other checkpoint inhibitors are being studied in various treatment settings in NSCLC. OAK has borne fruit, but there’s still a whole forest that remains yet to bloom.

References:

  1. Besse B, Johnson M, Janne PA, et al.; “Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC);” Eur J Canc, 51(s3): Abstract 16LBA, 2015.
  2. Vansteenkiste J, Fehrenbacher L, Spira AI, Mazieres J, Park K, et al., “Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR),” European Journal of Cancer, 51 (3): S716-S717, 2015.
  3. Barlesi F, “Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC,” ESMO Congress, Abstract LBA44_PR, Presidential Symposium 2, 2016.
  4. Califano R, Kerr K, Morgan RD, Lo Russo G, Garassino M, Morgillo F, Rossi A., “Immune Checkpoint Blockade: A New Era for Non-Small Cell Lung Cancer.” Current Oncology Reports, 18 (9), 2016.
  5. Kantar Health, CancerMPact® Treatment Architecture U.S. NSCLC, accessed October 9, 2016 from www.cancermpact.com

October 10, 2016 - 02:10 pm Posted in Uncategorized comments0 Comments

By Arnold DuBell, Ph.D., M.B.A., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

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Immunotherapies have justifiably generated a lot of buzz in 2016. For lung cancer, much has changed in the past year. U.S. and European agencies approved Keytruda® (pembrolizumab, MSD) for second-line therapy in all histologies of PD-L1+ patients as well as Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) for use in second-line patients with all histologies (staggered launches by histology; note that this approval does not require expression of the biomarker PD-L1). Japan’s Ministry of Health, Labour and Welfare (MHLW) took a broader approach for Opdivo and granted the agent approval for the treatment of unresectable, advanced and recurrent non-small cell lung cancer (NSCLC) patients.

At the 2016 European Society for Medical Oncology (ESMO) Congress, results of two trials in Sunday’s Presidential Symposium highlighted the continuing battle between these two PD-1 inhibitors as they move to the frontline setting. First up was what may be at least the temporary victor. The Phase III KEYNOTE-024 trial1 randomized 305 previously untreated Stage IV NSCLC patients with a PD-L1 TPS2 ≥ 50% to Keytruda (200 mg IV Q3W for two years) versus four to six cycles of platinum-doublet chemotherapy. A variety of platinum-doublet options were offered to physicians but were dependent upon tumor histology. If the patient had non-squamous histology and was offered Alimta® (pemetrexed, Eli Lilly) plus a platinum agent combination as a control, that patient could also be administered Alimta maintenance therapy. Patients who progressed after being treated with the control arm were allowed to cross over to receive Keytruda at the same dosing as described above.

KEYNOTE-024 met its primary progression-free survial (PFS) endpoint, improving PFS by 4.3 months (10.3 months versus 6.0 months, HR 0.50, p<0.001).   Of real note, since these data were an interim analysis, overall survival (OS) was also significantly improved in the Keytruda arm (medians not reached on either arm, HR 0.60, p=0.005). That this trial had met both of these endpoints had been known by the audience, as MSD announced the trial achieved its primary endpoint in a June 2016 press release, but this presentation was the first time the oncology community saw the magnitude of benefit. It was on the basis of an OS benefit at the interim that KEYNOTE-024 was stopped early by the trial’s data monitoring committee in June 2016. The overall response rate was also significantly improved in the Keytruda arm (45% versus 28%, p=0.0011).

Patients were treated for a longer time with Keytruda than chemotherapy (7.0 months versus 3.5 months). In spite of this longer exposure, Keytruda was better tolerated than chemotherapy (all grades: 73% versus 90%; Grade 3-4 adverse events: 26% versus 51%). Toxicities of note were nausea (10% versus 43%), anemia (5% versus 45%), fatigue (10% versus 27%), loss of appetite (10% versus 25%), vomiting (2% versus 23%) and neutropenia (1% versus 25%), which were all significantly decreased in the Keytruda arm; only pyrexia (Grades 1/2: 10% versus 4%) and diarrhea (all Grades: 14% versus 13%) were observed more frequently in the Keytruda arm compared with the chemotherapy arm.

At the end of this data presentation, the audience gave the presenter, Dr. Reck, a long and sustained ovation. This could not be said for Dr. Socinski, who next presented the results of the Phase III CheckMate 026 trial3 and received the usual polite ovation at his presentation’s end. CheckMate 026 randomized 541 patients to Opdivo 3 mg/kg Q2W versus histology-dependent chemotherapy.  Maintenance Alimta was also allowed, as was crossover to Opdivo following progression on the control arm. Unlike KEYNOTE-024, patients in CheckMate 026 were only required to have tumors with PD-L1 expression ≥1%.

Unfortunately, CheckMate 026 did not meet its primary PFS (based on immune-related response criteria, IRRC) endpoint in patients whose tumors expressed PD-L1 at ≥5% (4.2 months versus 5.9 months, HR 1.15, p=0.2511). Interestingly, the PFS curves separated early (with the chemotherapy arm performing better than the Opdivo arm) but then later converged on each other after about seven months post-randomization, perhaps speaking to late and/or sustained effects of immunotherapy.  Moreover, the OS in patients whose tumors expressed PD-L1 at ≥5% was not improved (14.4 months versus 13.2 months, HR 1.02), and the overall response rate was lower in these select patients treated with Opdivo (26.1% versus 33.5%).

The toxicity profile was improved with Opdivo, as there were fewer adverse events of any grade (71.2% versus 92.4%) and fewer Grade 3-4 adverse events (17.6% versus 50.6%). Common toxicities of all grades included fatigue (21.0% versus 35.4%), diarrhea (13.9% versus 12.9%), decreased appetite (12.0% versus 27.8%) and nausea (11.6% versus 48.3%).

The discussant to CheckMate 026, Dr. Rizvi, didn’t really have an explanation for why KEYNOTE-024 succeeded while CheckMate 026 didn’t. Although it may be that the molecules are ultimately just different – which is hard to justify given the preponderance of data in relapsed lung cancer and other tumors suggesting that in these other settings the efficacy benefits are similar – the best explanation lies in the design of the trial for CheckMate 026. It’s not the PD-L1 threshold difference, as subgroup analysis from CheckMate 026 suggested that patients whose tumors expressed PD-L1 at levels ≥ 50% also did not show significantly improved PFS or OS benefits. However, Dr. Rizvi did suggest some confusing issues in the trial design. First, he thought it very unusual that about 38% of patients had received prior radiation before enrolling in the trial. Moreover, he also thought that the time from diagnosis to initial treatment (two months) was rather long. Minor differences between the two trials were in the number of patients with squamous histology (19% in KEYNOTE-024 and 24% in CheckMate 026), slightly different choice of platinum doublets in the control arms of each trial (65% received Alimta-based in KEYNOTE-024 and 76% received Alimta-based in CheckMate 026), and subtle differences in the definition of the primary PFS endpoint (RECIST criteria for KEYNOTE-024, IRRC for CheckMate 026).

Based on these data, it is assumed that Keytruda will earn approval in the first-line setting and Opdivo will not. MSD has already filed with appropriate regulatory agencies for approval based on KEYNOTE-024. One unanswered question that was not addressed by these trials was whether physicians might sequence the agents – that is, use first-line Keytruda then second-line Opdivo.  Unfortunately, although both KEYNOTE-024 and CheckMate 026 allowed use of checkpoint inhibitors (either as crossover or as a true second-line therapy) for patients on the control arm, neither trial reported more than a handful of patients on the respective PD-1 inhibitor arm received checkpoint inhibitor therapy again in later lines. Therefore, all that can be surmised is that until new agents are approved, Keytruda will be used first-line in patients with PD-L1 expression ≥ 50%. The patients with expression less than that threshold will likely be offered a PD-1 inhibitor in the second-line setting; based on current trends, the preferred second-line PD-1 inhibitor is Opdivo,4 although it remains to be seen if the divergent results of these two first-line trials will lead to a shift in standards in second-line.

Other immunotherapies have recently entered the fray. The PD-L1 inhibitor Tecentriq® (atezolizumab, Genentech/Roche) presented positive data from the Phase III OAK trialat this conference,5 and this agent is expected to be approved soon for use in relapsed patients. The PD-L1 inhibitors durvalumab (MedImmune /AstraZeneca) and avelumab (Pfizer/Merck KGaA) as well as the CTLA-4 inhibitors Yervoy® (ipilimumab, Bristol-Myers Squibb/Ono Pharmaceuticals) and tremelimumab (MedImmune/AstraZeneca) are in Phase III trials for several settings in NSCLC.

However, this monotherapy competition was overshadowed somewhat with the presentation of a third abstract at Sunday’s Presidential symposium at the ESMO conference. Prior to the presentation of KEYNOTE-024, data from the Phase II KEYNOTE-021 trial’s cohort G were presented.6 This trial is a multicohort study of Keytruda-based combination therapies in advanced NSCLC. Cohort G evaluated four cycles of carboplatin plus Alimta with or without Keytruda (200 mg Q3W for two years) in 123 patients. As with the other trials, Alimta maintenance and crossover in the control arm were allowed.

KEYNOTE-021 met its primary overall response rate (ORR) endpoint, with a 26% improvement in the response rate (55% versus 29%, p=0.0016). There were no complete responses (CRs) in either arm. The time to response was numerically improved for patients treated with the Keytruda combination (1.5 months versus 2.7 months). Subgroup analyses were performed, stratifying the data based on PD-L1 expression. A difference in the response for Keytruda combinations was based on PD-L1 expression levels, with the highest rates observed in patients with TPS ≥50% (<1% PD-L1 expression, 57% ORR; ≥1% PD-L1 expression, 54% ORR; 1-49% PD-L1 expression, 26% ORR; ≥50% PD-L1 expression, 80% ORR). Interestingly, different responses were also seen in the chemotherapy-alone arm based on PD-L1 expression levels (<1% PD-L1 expression, 13% ORR; ≥1% PD-L1 expression, 38% ORR; 1-49% PD-L1 expression, 39% ORR; ≥50% PD-L1 expression, 35% ORR). PFS was a secondary endpoint but was improved by 4.1 months with the addition of Keytruda (13.0 months versus 8.9 months, HR 0.53, p=0.0102); this is similar to the level of benefit observed with Keytruda versus platinum doublet in KEYNOTE-026 but in a broader patient population according to PD-L1 status. OS data were very immature, and no OS benefit was reported (HR 0.90).

Treatment-related adverse events of all grades were roughly similar between the two arms (93% versus 90%); however, Grade 3-4 adverse events were increased with Keytruda (39% versus 26%). Unlike KEYNOTE-024, this increase may be due in part to the increase in the longer time of treatment for the Keytruda combination (median exposure time, 8.0 months versus 4.9 months) as chemotherapy was part of this regimen. Adverse events that increased in the Keytruda arm include fatigue (64% versus 40%), nausea (58% versus 44%), rash (27% versus 15%), vomiting (27% versus 18%) and diarrhea (20% versus 11%); anemia was increased in the chemotherapy-alone arm (32% versus 53%).

It is the data from KEYNOTE-021 that suggest that Keytruda may not be, as the discussant to this trial, Dr. Soria, noted, the “800-pound gorilla.” Although these data appear somewhat similar at first glance, Dr. Soria also noted that the Kaplan-Meier PFS curves for KEYNOTE-021 separated at about the one month time point while the KEYNOTE-026 curves separated after three months, suggesting gently that the future may lie in combinations of checkpoint inhibitors with chemotherapy or other immunotherapies. AstraZeneca has three such trials for combinations of durvalumab with tremelimumab (MYSTIC and NEPTUNE in the first-line setting; ARTIC for relapsed patients).  BMS has a Phase III trial, CheckMate-227, currently enrolling that looks at the combination of Opdivo alone, in combination with Yervoy, or in combination with chemotherapy, all compared with platinum-doublet chemotherapy. With these combination approaches being actively studied and potentially coming to market in the near future, Keytruda may not enjoy that “long ovation” for much longer. KEYNOTE-024 and CheckMate 026 are not the “end of the story” for immunotherapies for patients with NSCLC.

References: 

  1. Reck M, Rodriguez-Abreu D, Robinson AG, et al.; “KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%;” Annals Oncol, 27 (s1): Abstract LBA8_PR, 2016.
  2. TPS: tumor proportion score – percentage of tumor cells with membranous PD-L1 stainings.
  3. Socinski MA, Creelan B, Horn L, et al.; “CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator’s Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive NSCLC;” Annals Oncol, 27 (s1): Abstract LBA7_PR, 2016.
  4. Kantar Health, CancerMPact® Treatment Architecture U.S. NSCLC, accessed October 9, 2016 from www.cancermpact.com
  5. Barlesi F,  et al.; “Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC;” Annals Oncol, 27 (s1): Abstract LBA44_PR, 2016.
  6. Langer C, Gadgeel SM, Borghaei H, et al.; “Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G;” Annals Oncol, 27 (s1): Abstract LBA46, 2016.

October 10, 2016 - 02:10 pm Posted in Uncategorized comments0 Comments

By Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

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Approximately three-quarters of breast cancers are hormone receptor-positive (HR+) and thus express estrogen receptors, progesterone receptors or both. Endocrine therapy is the mainstay of therapy for patients with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Aromatase inhibitors (AI) are first-line standard of care for postmenopausal patients; however, the majority of women with advanced HR+, HER2-negative breast cancer develop disease that is resistant to these agents, and thus there is a great need for therapeutic agents that lengthen or restore sensitivity to endocrine therapy.

Growth of HR+ breast cancer depends upon cyclin D1, and cyclin D1 transcription is directly regulated through the estrogen receptor. Cyclin D1 activates cyclin-dependent kinases, including CDK4/6, which play a key role in cellular proliferation. To date, one selective CDK4/6 inhibitor, Ibrance® (palbociclib, Pfizer) is approved for treatment of HR+/HER2-negative advanced or metastatic breast cancer in combination with letrozole as initial endocrine-based therapy in postmenopausal women or in combination with fulvestrant in women with disease progression following endocrine therapy. Novartis is pushing for ribociclib (LEE011), through the MONALEESA-2 study, to become the next CDK4/6 inhibitor to market.

In May 2016, Novartis announced that the Independent Data Monitoring Committee recommended a halt to MONALEESA-2 as the trial had achieved its primary endpoint at a preplanned interim analysis; treatment with ribociclib plus letrozole showed a clinically meaningful improvement in progression-free survival (PFS) in 668 postmenopausal women who had received no prior therapy for advanced breast cancer. Results of MONALEESA-2 were presented today as part of the Presidential Symposium at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen.1,2 The Novartis-sponsored MONALEESA-2 trial is an international, placebo-controlled, Phase III trial that was designed to evaluate efficacy and safety of first-line ribociclib (600 mg/day, three weeks on/one week off) plus letrozole versus placebo plus letrozole in postmenopausal women with HR+/HER2-negative advanced breast cancer.  At the time of this presentation, the median PFS (investigator assessment) had not been reached for the ribociclib arm and was 14.7 months for the placebo arm (HR=0.556; p=0.00000329), the overall response rate was 41% versus 28% (p=0.000155), respectively, and survival data were immature. Ribociclib treatment benefit was consistent across all patient subgroups. The most common Grade 3/4 adverse events associated with ribociclib included neutropenia in 60% of patients (versus 0.9% in the placebo arm) and leucopenia in 21% (versus 0.6% in placebo arm); however, febrile neutropenia occurred in only 1.5% of ribociclib-treated patients. The majority of nonhematologic adverse events in the ribociclib arm were reversible by dose interruptions and reductions, and just 7.5% of patients required permanent discontinuation of both ribociclib and letrozole because of adverse events.

In August 2016, Novartis announced that, based upon MONALEESA-2 results, the U.S. Food and Drug Administration (FDA) had awarded ribociclib in combination with letrozole Breakthrough Therapy Designation in postmenopausal women who had received no prior therapy for their advanced disease. Regulatory filing plans have not been announced but are presumably under preparation.

As Ibrance is already approved in the United States and is expected to be approved in Europe shortly, ribociclib will likely be the second CDK4/6 inhibitor to market. In terms of clinical activity, these two CDK inhibitors appear to be very similar, both offering strong PFS benefits in comparison with letrozole alone and both with similar adverse event profiles.1,2,3 With such similar profiles, ribociclib may find difficulty displacing Ibrance, which has already been strongly adopted into practice in the United States after having been launched in February 2015. In Europe, Ibrance will have less of a time advantage over ribociclib, and the competition between these two CDK4/6 inhibitors may be a tighter race. To help differentiate ribociclib from Ibrance, Novartis has initiated two additional Phase III studies, MONALEESA-3, to evaluate the combination of ribociclib plus fulvestrant in first or second line (similar in design to the PALOMA-3 trial for Ibrance4), and MONALEESA-7, to evaluate ribociclib plus tamoxifen plus goserelin in pre/perimenopausal women with advanced breast cancer (a unique indication from any of the other CDK inhibitors in development).

References:

  1. Hortobagyi GN et al., “First-line ribociclib + letrozole for postmenopausal women with HR+, HER2-, advanced breast cancer: first results from the phase III MONOLEESA-2 study.” Annal Oncol, 27 (s1): Abstract LBA1_PR, 2016.
  2. Hortobagyi GN, Stemmer SM, Burris HA, et al., “Ribociclib as first-line therapy for HR-positive, advanced breast cancer.” New Engl J Med. Published on line on October 8, 2018; DOI: 10.1056/NEJMoa1609709.
  3. Finn RS, Martin M, Rugo HS, et al.; “PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC);” J Clin Oncol 34, 2016 (suppl; abstr 507).
  4. Turner NC, Ro J, Andre F, et al.; “Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer;” New  Engl J Med,  2015, DOI: 10.1056/NEJMoa1505270.

October 04, 2016 - 10:10 pm Posted in Uncategorized comments0 Comments

Among the 10 ambitious priorities a blue ribbon panel forwarded to the Cancer Moonshot Task Force, headed by Vice President Biden, the call for accelerated research to identify approaches to monitor and manage patient-reported symptoms and other patient-reported outcomes (PRO) brings this topic further prominence. This echoes a central theme at this year’s ASCO Annual Meeting, and the focus of an Executive Roundtable held during the meeting on patient-strategies for oncology research and treatment.

It may be surprising that symptom management and the use of PRO in cancer care hasn’t received more attention over the years, given that cancer is a disease of symptoms. Both disease symptoms (pain, fatigue, shortness of breath and loss of weight, among others) and toxicities of treatment have a disproportionate impact on the experience of someone with cancer relative to most other medical conditions. To date, clinical care and drug research have focused far more on outcomes like tumor growth or shrinkage, biomarkers, and measures of overall or progression-free survival, when in fact we are learning that patients may be willing to trade some measure of traditional outcome for relief from treatment-related symptoms, like fatigue, that would improve their quality of life.

As the 2016 CancerCare Patient Access and Engagement Report found, there is an “impact gap” in communication between patients and their clinical care teams. The survey found that in discussions with care providers, about half of patients downplayed their side effects and symptoms. Nearly 40% did not report symptoms or side effects because they did not want to “bother” their doctors. Making symptoms management a higher priority in the clinical encounter would facilitate these conversations between patients and the care team, in both directions.

It is incumbent on clinical development researchers to consider how best to measure the impact of new therapy on outcomes that matter to patients in order to support the overall Value assessment of the drug under study. This will require expertise in selecting appropriate, valid measures of relevant symptoms. Furthermore, regulatory agencies are increasingly engaging with multiple stakeholders to support consideration of the voice of the patient in their decisions.

The spotlight that’s being shone on this issue – and the potential research and implementation funding that may ensue – couldn’t come at a more pivotal moment for cancer research and treatment.

By Joe O’Connell, M.D., Vice President and Global Therapeutic Lead, Medical Affairs, inVentiv Health

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September 28, 2016 - 04:09 pm Posted in Uncategorized comments0 Comments

By Cory Lewis, Ph.D., Manager, Clinical & Scientific Assessment, Kantar Health

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We are in a unique time within cancer therapy, where significant resources are being used to develop drugs that target the immune system to fight cancer. Now we embark on a new endeavor in which most of the work is not discovering novel agents but developing a better understanding how to improve the use of therapies we have available.

Most of us are well aware of immunotherapy and its rise among the ranks of more than 3,400 cancer therapies. Immunotherapies targeting the immune checkpoint in cancer have led to the approval of Keytruda® (pembrolizumab, Merck), Opdivo® (nivolumab, Bristol-Myers Squibb), Yervoy® (ipilimumab, Bristol-Myers Squibb) and Tecentriq® (atezolizumab, Roche).

These immune checkpoint therapies are designed to inhibit those molecules that prevent the immune system pathway from acting on cancer cells, while immune costimulators are designed to activate the immune system.

Immune costimulators work by providing the signal that promotes the expansion and proliferation of killer CD8 and helper CD4 T-cells. While immune checkpoint therapies are “releasing the brakes,” costimulators are “stepping on the gas.” Both mechanisms are required for a robust immune system response.

The hope is that by combining checkpoint inhibitors with immune costimulators the immune response will be more robust and response rates will drastically increase. Many combinations are being evaluated to fine tune the immune system response while minimizing side effects.

Kantar Health’s newly developed CancerLandscapeTM platform identifies 23 immune checkpoint-targeted therapies in 893 trials in development, including 12 immune costimulators in 41 trials. Targets for immune costimulators include CD40L, GITR, 4-1BB, CD27, TNFRSF25, TMIGD2, ICOS, CD28 and OX40. Of this group, OX40 is the target furthest in development with over 12 ongoing clinical trials.

With all the new therapies and potential targets along with endless combination options it will be hard to decide which combinations are best to develop.

Some of these details are already being investigated:

  • The number of  times the immune system can be activated and still get a response
  • The stage of cancer in which it is best to use immunotherapy
  • The sequence of immunotherapy (i.e., CTLA4 then PD-L1, costimulators then checkpoint inhibitor,  vice versa, or both)

These details are currently being investigated in animal models and in the clinic and are important to the patients and their response to immunotherapy. The hope would be we can even unlock tumors not thought to be able to respond to immunotherapies by perfecting the system. The surface has just been touched when it comes to costimulators, and we all await the answers.

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