By Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
The treatment armamentarium available for patients with advanced melanoma has become quite well stocked as recent progress in the development of novel therapeutic agents has been tremendous. Immune checkpoint inhibition and targeted inhibition of BRAF and MEK are two therapeutic approaches that have significantly improved survival for patients with advanced melanoma. Since 2011, the Food and Drug Administration(FDA) has approved three checkpoint inhibitors, starting with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb/Ono Pharmaceuticals), followed by subsequent approvals of programmed death-1 (PD-1) receptor inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals); for patients whose tumors harbor a BRAF mutation, the BRAF inhibitors Zelboraf® (vemurafenib, Roche/Plexxikon/Daiichi-Sankyo) and Tafinlar (dabrafenib, Novartis) and the MEK inhibitor Mekinist (trametinib, Novartis) round out the armamentarium.
Opdivo holds the title of the first PD-1 inhibitor to gain global regulatory approval when it was approved in Japan in July 2014 for metastatic melanoma. In September 2014, Keytruda became the first PD-1 inhibitor to gain approval in the U.S. when the FDA awarded it accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. However, the race to the U.S. market was tight as Opdivo received accelerated approval from the FDA in December 2014 for a similar indication.
With both Keytruda and Opdivo approved for refractory melanoma, the battle has shifted to treatment-naïve advanced melanoma, where Yervoy has ruled as the only approved checkpoint inhibitor in the U.S. since 2011. However, recent data from the Phase III KEYNOTE-006 trial demonstrated the superiority of Keytruda over Yervoy with regard to significant progression-free survival (PFS) and overall survival (OS).1 Thus, it is evident that the dominance of Yervoy monotherapy as front-line treatment for BRAF-wildtype patients will soon fade away.
The next logical step to consider is combinations of checkpoint inhibitors. Immune checkpoints play critical roles in balancing co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T-cell responses. CTLA-4 and PD-1 are distinct yet complementary pathways that inhibit antitumor immunity. Published Phase I and II data already suggest that simultaneous blockade of both pathways with Yervoy and Opdivo may be more active than either monotherapy alone.2,3
Today, preliminary results from the phase III CheckMate-067 trial were reported in the Plenary Session of the annual meeting of the American Society for Clinical Oncology (ASCO).4,5 This trial is evaluating the impact of combining two immunotherapies, Opdivo and Yervoy, versus either single agent in treatment-naïve patients with Stage III (unresectable) or Stage IV melanoma. Patients were randomized (1:1:1) to receive Opdivo alone (3 mg/kg every two weeks, plus a Yervoy-matched placebo), versus Opdivo (1 mg/kg) in combination with Yervoy (3 mg/kg) administered every three weeks for four doses followed by Opdivo alone (3 mg/kg every two weeks) until disease progression, versus Yervoy alone (3 mg/kg every three weeks for a total of four doses, plus an Opdivo-matched placebo). OS and PFS are co-primary endpoints.
Treatment with the combination of Opdivo plus Yervoy or with Opdivo monotherapy yielded superior clinical activity compared to treatment with Yervoy alone. Median PFS were 11.5 months (Opdivo + Yervoy; HR 0.42 and p<0.00001 vs. Yervoy), 6.9 months (Opdivo; HR 0.57 and p<0.00001 vs. Yervoy) and 2.9 months (Yervoy). Objective response rates were 57.6% (Opdivo + Yervoy; p<0.00001 vs. Yervoy), 43.7% (Opdivo; p<0.00001 vs. Yervoy) and 19.0% (Yervoy). Quite disappointingly, OS data are immature and were not presented. PFS was also analyzed in prespecified subgroups of patients according to PD-L1 expression. Among patients with PD-L1-positive tumors (defined as ≥1% PD-L1-positive tumor cells) the median PFS was 12.4 months for both the Opdivo + Yervoy arm and the Opdivo-alone arm, which was strongly improved compared to the 3.9–month median PFS for patients treated with Yervoy alone. Patients with PD-L1-negative tumors (<1% PD-L1-positive tumor cells) had median PFS of 11.2 months (Opdivo + Yervoy), versus 2.8 months (Opdivo alone) versus 2.8 months (Yervoy alone). Improved clinical efficacy of the combination comes at a cost, however. Drug-related Grade 3/4 adverse events were reported in 55% of patients in the combination arm versus 16.3% in the Opdivo-alone arm and 27.3% in the Yervoy-alone arm. Approximately 36% of patients in the combination arm discontinued treatment due to toxicity, compared to only 8% of patients treated with Opdivo monotherapy and 15% of patients treated with Yervoy monotherapy. Interestingly, a majority of patients who required a treatment discontinuation actually developed an objective tumor response after drug discontinuation.
Results from this trial are practice changing, and now either Opdivo + Yervoy or a PD-1 checkpoint inhibitor alone (Keytruda or Opdivo) should be considered standard of care for front-line BRAF wildtype melanoma. Although the efficacy of dual checkpoint pathway blockade is impressive, management of toxicity and patient selection remain challenges. Greater effort is needed to develop biomarkers/assays that will identify those patients who are likely to respond and those who are not. PD-L1 expression is a weak biomarker, and current assays are technically difficult and imperfect, especially for patients with low PD-L1 expression. The need for a better biomarker assay is particularly important when considering that Yervoy + Opdivo is associated with Grade 3/4 toxicity in 55% of patients. In patients where tolerance of toxicity is a key consideration, a PD-1 checkpoint inhibitor monotherapy may be the appropriate choice. Furthermore, appropriate patient selection is critical with regard to cost of therapy. Opdivo + Yervoy has an annual price tag in excess of $180,000, further necessitating the development of an assay to differentiate between potential responders and non-responders to contain costs (although Dr. Jedd D. Wolchok made a point at the end of his presentation to advertise a BMS-sponsored expanded access program now available for this combination, which may alleviate the financial burden in the short term ahead of FDA approval). Other alternatives may also help ease the disadvantages of this regimen. Could a lower dose of Yervoy (such as two doses rather than four) be equally efficacious but help reduce both toxicity and the cost of dual checkpoint inhibitor therapy? We also don’t yet know if the observed PFS benefit will also translate into an OS benefit. While hope is high that dual checkpoint blockade will raise the survival curve plateau (how high can it go?), would we achieve the same OS outcomes if both drugs are combined in first-line compared with their use in sequential lines of therapy? Unfortunately, this remains a blackbox since not even a hint of OS outcomes were reported at today’s Plenary Session.
While development of checkpoint inhibitors has revolutionized melanoma treatment and dual checkpoint therapy appears very promising, balancing safety, efficacy and cost requires further consideration, and there is a long way to go toward identification of patients who are best suited to this combination therapy.
By Linda Zhao, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Two important drugs obtained approval from the Food and Drug Administration (FDA) last year for use in relapsed/refractory chronic lymphocytic leukemia (CLL): Imbruvica® (ibrutinib, Pharmacyclics/Janssen) as a single agent in February 2014 and Zydelig® (idelalisib, Gilead) in combination with Rituxan® (rituximab, Genentech/Roche) in July 2014. Still, better treatment options with greater therapeutic outcomes are strongly needed in CLL treatment to prolong survival in these patients.
Imbruvica is a covalent inhibitor of Bruton’s tyrosine kinase (BTK), which is involved in the maturation and activation of B-cells and is implicated as a driver of B-cell related lymphomas and leukemias. Pharmacyclics and Janssen are aggressively developing Imbruvica in CLL across multiple lines of therapy and are looking beyond its recent approval as monotherapy and hoping that combining Imbruvica with the standard-of-care chemotherapy backbone in second-line – Rituxan plus Treanda (bendamustine, Teva/MundiPharma/Eisai), the BR regimen – will yield stronger clinical benefits over R-Treanda alone in the relapsed/refractory setting.
In September 2012, Janssen initiated the Phase III placebo-controlled HELIOS trial (NCT01611090) to evaluate the safety and efficacy of BR (up to six cycles) with or without Imbruvica (given until disease progression) in relapsed or refractory CLL or small lymphocytic lymphoma (SLL) patients; patients with del17p (> 20% of cells) were excluded. The trial completed enrollment of 578 patients in February 2014. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include objective response rate (ORR), overall survival (OS), rate of minimal residual disease (MRD)-negative remissions, quality of life, and adverse events. In March 2015, Janssen announced that the independent data monitoring committee (IDMC) unanimously recommended unblinding the HELIOS trial, citing that the study met its primary endpoint by demonstrating a significant improvement in PFS in favor of the Imbruvica arm. Today, the much anticipated results from this trial were reported in Chicago at the American Society for Clinical Oncology (ASCO) annual meeting by Dr. Asher Alban Akmal Chanan-Khan as a Late Breakthrough Abstract oral presentation.1
The pre-planned interim analysis reported today confirmed the positive news as stated in the company’s news release. Enrolled patients had received a median of two prior lines of therapy and had a median age was 64 years old, and 38% of patients were Rai Stage III/IV. At a median follow-up of 17.2 months, the IDMC-assessed median PFS in the Imbruvica + BR arm was significantly longer than the control arm (not reached in the Imbruvica + BR arm vs. 13.3 months in the BR arm, HR: 0.203p< 0.0001). The PFS results were consistent across all subgroups analyzed. The ORR and complete remission (CR/CRi) rates were also significantly improved in the Imbruvica arm: 82.7% versus 67.8% and 10.4% versus 2.8%, respectively. Even though the median OS were not reached in either arm at the time of interim analysis, the survival curves suggest a benefit in favor of the Imbruvica + BR arm (HR 0.628, p=0.0598). This trend to OS benefit is all the more encouraging considering that patients with confirmed progressive disease in the BR + placebo arm were allowed per protocol to cross over to receive Imbruvica (a fact that may ultimately confound the ability to reach statistical significance).
Most adverse events (AEs) were similar between the two arms. The most common all-grade AEs were neutropenia (58.2% in the Imbruvica + BR arm vs. 54.7% in the placebo + BR arm) and nausea (36.9% in vs. 35.2%); the most common Grade 3/4 AEs were neutropenia, also similar in the two arms (53.7% vs. 50.5%), and thrombocytopenia (15.0% each arm). Rates of Grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhages occurred in 2.1% and 1.7% of patients, respectively.
The BR regimen is commonly used in second-line CLL (among patients who don’t receive single-agent Imbruvica) and is the most commonly used regimen used in the first-line setting. The addition of Imbruvica to this standard backbone regimen reduced the risk of progression or death by 80%, with few additional AEs (although with a slight increase in Grade 3/4 atrial fibrillation). The results reported here strongly confirm Imbruvica as an important treatment option for patients with previously treated CLL/SLL and pave the way to significantly expanded use of Imbruvica in relapsed/refractory disease and may even support the use of the Imbruvica + BR regimen in front-line. The excitement driven by the efficacy benefit seen in HELIOS is heightened by the fact that the safety profile with Imbruvica + BR is not worse than the safety profiles from Imbruvica or BR alone; this could alleviate physician concern regarding exacerbated side effects usually seen when two drugs are combined. Overall, the success of the HELIOS trial will significantly expand the commercial opportunity for Imbruvica in CLL, and it’s just the beginning: HELIOS is just one of the six pivotal trials of Imbruvica ongoing for CLL treatments. Ultimately it will maximize the commercial opportunities for Imbruvica if its use in combination with the BR regimens will displace the use of traditional chemotherapy in the second-line setting or expand its use into front-line.
The question raised by the discussant, Professor Lloyd Damon from the University of California San Francisco, was whether the HELIOS trial has asked the best question for CLL treatment. Dr. Damon compared the results of HELIOS with several other single-arm studies: an earlier Phase II trial of Imbruvica + BR2 and a combined analysis of several single-agent Imbruvica studies,3 citing the similarities between patient baseline features, prior regimens, ORR, CR, as well as the median PFS between these three studies. Dr. Damon suggested that the implication of the HELIOS trial may lie in whether chemotherapy can be omitted as first treatment for CLL/SLL. This issue is being explored in the ongoing Phase III ECOG E1912 study (which compares R-Imbruvica versus the historical R-FC (fludarabine and cyclophosphamide) regimen in previously treated patients) and the ALLIANCE A041202 trial (which compares Imbruvica versus R-Imbruvica versus BR alone in previously untreated elderly patients). Success in these trials could lead to a revolutionary change in CLL treatment. Of course, Gilead is also seeking to expand the role of Zydelig in CLL and has several ongoing randomized studies that will keep it in direct competition with Imbruvica across all lines of therapy.
With the recent introductions of Imbruvica, Zydelig, and Gazyva® (obinutuzumab, Genentech/Roche), the CLL treatment landscape has already changed drastically from just 15 months ago. The results from HELIOS today will support even further change, and with the number of ongoing Phase III trials for these agents as well as several other promising new drugs, outcomes for patients with CLL are beginning to look very bright.
By Arnold DuBell, Ph.D., M.B.A., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Non-small cell lung cancer (NSCLC) is one of the tumor types with the highest unmet need, representing the most commonly diagnosed cancer globally1 and one that is frequently diagnosed at an advanced stage,2 where prognosis is most dire. As such, NSCLC has long been a focus of significant clinical development and currently is a poster child for personalized medicine; treatment varies significantly depending on a patient’s tumor histology and their biomarker status (EGFR mutation and ALK translocation are currently the key biomarkers guiding clinical decision making, although many others are under study).
The most recently approved agent for the treatment of NSCLC is Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals), which was approved by the FDA in March 2015 for squamous metastatic NSCLC patients who have previously received a platinum-based therapy. This approval was based largely on a single-arm Phase II trial, supplemented by randomized Phase III data (the CheckMate-017 trial) that will be reported publicly for the first time at the American Society for Clinical Oncology (ASCO) annual meeting tomorrow. The approval in squamous histology is the first targeted therapy approved for this subset of patients, representing a major advance in their disease management. However, squamous NSCLC represents only a fraction (approximately 25%) of all NSCLC, leaving the majority of NSCLC patients who have non-squamous disease with an unknown level of benefit from this PD-1 inhibitor.
One of the most anticipated data from ASCO 2015 are the results of CheckMate-057, the Phase III trial that compares Opdivo versus docetaxel as second-line therapy for patients with non-squamous metastatic NSCLC.3 This trial randomized 582 patients to treatment with 3 mg/kg q2w Opdivo or 75 mg/m2 q3w docetaxel, both administered until disease progression or unacceptable toxicity. In the intent-to-treat (ITT) population, Opdivo significantly improved overall survival (OS) compared to docetaxel. OS is the gold standard by which to judge activity, and Opdivo resulted in a 27% reduction in the risk of death, which amounted to a 2.8-month difference at the median (12.2 months vs. 9.4 months, HR 0.73, p=0.0015). Importantly, the survival curve plateaued, with the one-year OS rates significantly differing between the two treatment arms (51% vs. 39%) and the curves continuing to separate even at later time points (18-month OS is approximately 40% vs. 20%, although there are still a large number of censored patients at this time point). No new safety signals were observed, and no single adverse event occurred in more than 1% of patients. However, the ITT population showed no progression-free survival (PFS) benefit (median PFS 2.3 months vs. 4.2 months, HR 0.92, p=0.3932). Interestingly, both the PFS and OS curves crossed, and the Opdivo arm eventually showed more patients progression-free at one year than those treated with docetaxel (19% vs. 8%). These results in the ITT population appear to be slightly less robust than the data for Opdivo in squamous patients, as reported for the CheckMate-017 trial to be presented later during ASCO.4
While it was exciting to see an OS benefit in the broad population of non-squamous NSCLC patients, the real story was the secondary endpoint of outcomes according to PD-L1 biomarker status. Patients were not required to overexpress the ligand for study entry but were required to have tissue available for secondary analysis and stratification. The majority (78%) of enrolled patients had tumor samples with quantifiable PD-L1 expression. When OS was evaluated by PD-L1 expression status, a clear and large benefit was associated with biomarker overexpression, and no OS benefit was seen in patients with less than 1% PD-L1 expression. Additionally, the magnitude of OS benefit (measured as the Hazard ratio; please refer to the table below) appeared to gain significance when higher thresholds of PD-L1 positivity were assessed. A similar association between activity and threshold of PD-L1 positivity was observed with regard to PFS and response rate outcomes.
These results present a bit of a conundrum. In one sense, the trial met its primary endpoint in the ITT population, showing a significant OS benefit for pretreated non-squamous NSCLC patients regardless of biomarker status. This could support FDA approval in such a broad population, and indeed its current approval in squamous NSCLC is not limited by biomarker (we hope to learn at tomorrow’s presentation of CheckMate-017 whether a correlation exists with biomarker status in that patient population). Use of Opdivo in the ITT population without limitation by PD-L1 status was supported by Dr. Roy Herbst, who discussed the CheckMate-057 data. He argued that the biomarker isn’t ready for prime time, for a number of reasons. On the other hand, the lack of any benefit in patients with less than 1% PD-L1 expression makes a strong case for not using Opdivo in these patients, especially given the high cost of this therapy (in and of itself, but also when compared to generic docetaxel).
Two clear arguments emerge in favor of using Opdivo regardless of biomarker status. First, it is clearly better tolerated than docetaxel, with very few Grade 3/4 adverse events observed with Opdivo, and docetaxel is characteristically associated with myelosuppression. Therefore, even in a patient with no PD-L1 expression, Opdivo could be viewed as an equally effective and better tolerated treatment option. The second argument, and the one that is the subject of the most debate, is the reliability of the PD-L1 diagnostic assay and how and when it is evaluated. The majority of patients in CheckMate-057 had archival tumor tissue that was evaluated for the biomarker. Knowing that tumors evolve over time, how accurate is it to categorize a patient’s biomarker status for treatment in second-line based on an assay that was performed on tumor tissue collected potentially much earlier in the course of their disease? Additionally, tumors are notoriously heterogeneous, both within the same lesion as well as comparing primary and metastatic lesions. Can we be sure a patient is truly PD-L1-negative based on lack of overexpression in a single tumor sample? Although Dr. Herbst was particularly vocal about this point during his discussion, this same argument can be made about most biomarkers used in oncology today, and yet we don’t argue that EGFR wildtype NSCLC or KRAS-mutant colorectal cancer patients should be treated with Tarceva® (erlotinib, OSI/Astellas/Roche) or Erbitux® (cetuximab, Eli Lilly/Merck KGaA), respectively. Why should we treat the PD-L1 biomarker any differently? One reason to offer Opdivo to PD-L1-negative patients may be the potential lost long-term OS benefit if an active drug is withheld from a patient based on the results of an imperfect assay.
Clearly the issue of PD-L1 as a necessary biomarker in NSCLC continues to be a subject of debate. Data to be presented later at this conference for other checkpoint inhibitors will add to the body of data for this, but the final answer is unlikely to emerge before the conference concludes. However, the data will add complexity to the treatment paradigm and has the potential to change the rules of the game when it comes to PD-1 and PD-L1 inhibitors. The results of CheckMate-057 clearly establish Opdivo as a new standard of care for second-line NSCLC. What remains to be determined is for how many of those patients?
1) Globocan 2012, available from globocan.iarc.fr; accessed May 30, 2015.
2) Kantar Health, CancerMPact Patient Metrics, available from www.cancermpact.com; accessed May 30, 2015.
3) Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr LBA109).
4) Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33: (suppl; abstr 8009).
The new partnership announced today between Varian Medical Systems and Flatiron Health hits on many of the keywords in the digital space these days, including cloud-based technology, EHR, data analytics, and decision-support software. Varian is known as a market leader in radiation oncology software and Flatiron acquired Altos who makes the leading web-based oncology-focused EMR, called OncoEMR. But with the pairing of these two companies, we wondered if it is all about strength in marketing, big data, or is it about synergies to help provide oncologists with new tools and improve quality cancer care? OBR talked to Sukhveer Singh, Vice President, Oncology Continuum Solutions, Varian Medical Systems and Zach Weinberg, Co-Founder, President, and COO at Flatiron to see if we could better understand the underpinnings of the alliance.
Both companies consider themselves market leaders in their respective specialties: Varian in radiation oncology and Flatiron in oncology-specific EMRs. Varian publicly states that the ARIA platform is used in more than 3,400 radiation oncology centers worldwide, while Flatiron states that there are over 220 community oncology practices and/or cancer centers using OncoEMR. By partnering, they hope to build upon their respective areas of expertise and provide a comprehensive suite of products that encompass radiation oncology, medical oncology, and data analytics. “We want to leverage the complementary nature of our products” said Mr. Singh.
According to Singh, “the ARIA software platform provides solutions for managing patient care and treatments. Historically, we have been responsible for most of the innovations in radiation oncology software. That is what we want to build upon now.”
Regarding the partnership, Mr. Weinberg told us, “we offer two different products for the oncology provider – a cloud-based oncology EHR called OncoEMR, and a data analytic tool called OncoAnalytics, which helps providers with their day-to-day decision making. Both companies are addressing provider-facing problems in any setting, whether academic or community based, and are hoping the partnership will address problems across the continuum of care in radiation and medical oncology.”
What are those problems that the partnership hopes to solve?
Mr. Weinberg describes the silos in oncology as radiation oncology, surgical oncology, medical oncology, and other care providers that are not easily sharing information. The hope is that this partnership will allow cross-communication and breakthrough each of those silos resulting in improved care.
How, specifically, do they intend to help physicians break down the silos?
“The partnership is about product integration, about making OncoEMR interoperable with all the products in the ARIA software suite. We want to make all of these ‘best of breed’ services work together seamlessly,” said Weinberg.
“The most exciting thing is where we want to go together. We believe that software, informatics, and analytics, can become the backbone of a patient’s journey from diagnosis to survivorship,” said Singh.
Weinberg agrees, “you can see both the depth and breadth from this partnership – breadth in terms of the number of customers that the combined offering will cover, and depth because we will now start to see data across the continuum, and not just medical or radiation oncology data.”
Adding value to the continuum of care
Cancer patients are treated by more than one specialty, meaning medical oncologists, radiation oncologists, and surgical oncologists, in addition to a psychiatrist, dietician and other members of the treatment team. Varian and Flatiron feel the value in this partnership is in care coordination.
According to Weinberg, the value in this integration from the medical oncology standpoint can be as basic as “did my patient receive the radiation treatment they were scheduled to receive?” to the seamless workflow across the patient care continuum which benefits both providers and patients.
Regarding analytics, Weinberg says, “the key with analytics is having a full picture of the patient… Over time, all of the medical oncology and radiation oncology data will flow into a central place. And then both companies will be offering different analytic solutions depending on the problem at hand. In that way, analytics will become enhanced regardless of which company is offering them because the two systems are interoperable.”
Singh noted that “this is a unique value proposition because we are making decision support accessible at the point of care. We are working toward a rapid cycle of gathering high-quality data, converting that data into insights, and making those insights available to the physicians at point of care when the patient is being treated.”
Physicians will still be able to purchase ARIA and/or OncoEMR separately, depending on what is best for the customer. The brand names will stay the same. Initially, the focus will be in the United States, but all of the product enhancements will be offered internationally as well.
by Don Sharpe