The OBR Blog

June 05, 2016 - 12:06 am Posted in ASCO Conference Coverage comments0 Comments

By: Madelyn Hanson, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

Therapeutic approaches for acute myeloid leukemia (AML) have gone unchanged for several years. Most newly diagnosed patients achieve complete remission (CR) with a combination regimen of cytarabine plus an anthracycline (7+3 most commonly). However, the high rate of CR comes at the cost of a high level of toxicities with this regimen. This poses a significant problem for the multiple subsegments within AML that have a poor prognosis, such as elderly patients, those with specific molecular aberrations, and patients with various comorbidities. Often these patients cannot tolerate the high toxicities that accompany the 7+3 regimen, which leaves only less efficacious treatment options for these patient subsegments. Hypomethylating agents (HMAs) that are approved for the treatment of myelodysplastic syndromes (MDS) ‒ such as Dacogen® (decitabine, Eisai/Janssen) and azacitidine ‒ are often used to treat these patients.

More recently, these patients with high unmet need have become a hotbed for new therapy development. Exciting results presented at the 2015 annual meeting of the American Society of Hematology (ASH) demonstrated that the FLT3 inhibitor midostaurin (Novartis) combined with 7+3 was able to triple overall survival (OS) in newly diagnosed FLT3+ AML patients.1 Other agents currently being evaluated in Phase III trials for relapsed/refractory FLT3+ AML include quizartinib (Daiichi Sankyo) and enasidenib (AG-221, Agios/Celgene). While these agents have created a great deal of excitement for FLT3+ patients, even more development is ongoing for the treatment of elderly patients with AML. While the definition of “elderly” is not based strictly on chronological age but more often biologic age (which takes into account patient “fitness”), more than half of AML patients are still considered to be “elderly” (according to surveyed U.S. physicians2), signifying that this is a large patient population with a high unmet need. VYXEOS (CPX-351, Celator), ganetespib (Synta Pharmaceuticals), guadecitabine (SGI-110, Otsuka/Astex), sapacitabine (Cyclacel), vadastuximab talirine (SGN-CD33A, Seattle Genetics), and volasertib (Boehringer Ingelheim) are all in late-stage development for newly diagnosed, elderly patients.

Today at the annual meeting of the American Society for Clinical Oncology (ASCO), final results were presented from a Phase III trial (NCT01696084) evaluating VYXEOS in untreated, elderly AML patients considered at high risk for recurrence.3 VYXEOS is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio. This formulation is administered intravenously at 100 u/m2 on days 1, 3 and 5 by approximately 90-minute infusion compared with the standard 7+3 regimen, which requires continuous infusion of cytarabine (100 mg/m2/day) for seven days as well as of daunorubicin (60 mg/m2) on days 1, 2 and 3.

In the trial, VYXEOS was compared with the standard 7+3 regimen of cytarabine and daunorubicin as first induction in untreated elderly patients with high-risk or secondary AML. The study enrolled 309 patients and OS was the primary endpoint. VYXEOS met its primary endpoint with mOS of 9.56 months compared with 5.95 months for patients receiving 7+3 therapy (HR=0.69, p=0.005). A 1.22-month improvement in event-free survival (EFS) also was observed in the VYXEOS arm (2.53 vs. 1.51 months, HR=0.74, p=0.021). VYXEOS was shown to improve the overall response rate (CR+CRi of 47.7% vs. 33.3%; p=0.016), with a significant improvement in CR (37.7% vs. 5.6%, p=0.040) and EFS (HR= 0.74, p=0.021).

Subanalysis of OS in patients with or without transplant was also performed. Although the sample was small (n=91), the mOS of patients who went on to receive a stem cell transplant following induction was significantly improved in the VYXEOS arm compared with the 7+3 arm (not reached vs. 10.25 months, HR=0.46, p=0.0046).

To begin to evaluate tolerability of VYXEOS, 60-day mortality favored VYXEOS versus 7+3 (13.7% vs. 21.2%). However, the presenter noted that while there was a significant reduction in deaths due to progressive AML (3.3% vs. 11.3%), there was no difference in deaths due to adverse events between the two arms (10.4% with VYXEOS vs. 9.9% with 7+3). Thus, the 60-day mortality improvement likely reflects the improvement in efficacy and not a difference in safety signals between the two regimens. In fact, there was no difference in Grade 3-5 adverse events between the two arms of the study. In addition, in patients achieving a CR after one induction, patients in the VYXEOS arm had a median six-day delay in absolute neutrophil count recovery compared with the 7+3 arm and a 7.5-day delay in platelet count recovery.

VYXEOS was awarded the U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation in May 2016, and Celator intends to submit a new drug application with the FDA later this year based on the data reported. Efficacy results from this study suggest that VYXEOS could quickly change the treatment approach for newly diagnosed, elderly AML patients that are deemed high risk. The fact that VYXEOS is a liposomal formulation of two agents (cytarabine and daunorubicin) that are currently standard of care for AML also supports rapid uptake by physicians. However, the issues of tolerability with the 7+3 regimen in elderly patients remain with VYXEOS. Physicians will have to decide whether the efficacy achieved along with the adverse-event profile warrants use of VYXEOS in individual patients. Although not discussed, additional subanalyses from this trial could provide physicians the information they need to select the patients most likely to benefit from VYXEOS. Although this trial was not performed in low-risk or younger patients, there may be a desire among physicians to use VYXEOS in these other patient types to improve the ability to reach stem cell transplant and improve OS, although such use would be considered off-label.

Thus, while VYXEOS sets a high survival benchmark in elderly, high-risk AML patients, this cytotoxic agent still leaves some room for targeted agents such as volasertib (which targets polo-like kinase), ganetespib (which targets heat-shock protein 90), and vadastuximab talirine (which targets CD33) with potentially less toxicity to enter into the same space if they too can demonstrate significant survival benefits, although notably these drugs are all being compared with low-intensity, single-agent therapies in their ongoing pivotal trials.

References:

  1. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Plenary session, Abstract 6, American Society of Hematology Meeting, December, 2015
  2. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 6, 2016.
  3. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol 34, 2016 (suppl; abstr 7000).

 

May 11, 2016 - 06:05 pm Posted in ASCO Conference Coverage comments0 Comments

By Jay Grisolano and Co-authored by Tari Awipi, PhD and Stephanie Hawthorne, PhD, Kantar Health

With the annual meeting of the American Society of Clinical Oncology (ASCO) quickly approaching (June 3-7, Chicago), the 2016 event is sure to live up to its reputation for delivering market-changing data and trends from the world of oncology. Below, Kantar Health spotlights four potentially noteworthy abstracts that are likely to generate much discussion and significantly influence patient care. For a complete assemblage of all nine of Kantar Health’s top abstracts of interest, please see the associated article in the May issue of OBR Green.

Vyxeos as induction for older patients with untreated high-risk (secondary) AML

Management of acute myeloid leukemia (AML) has been largely unchanged over several decades, with first-line induction therapy typically consisting of a combination regimen of cytarabine plus an anthracycline (7+3 most commonly).1 This is a very intensive regimen, and while it is effective at inducing remissions in a high proportion of patients, several subsets of AML patients exist with unmet needs. In patients with high-risk AML, which includes cytogenetic abnormalities as well as those with secondary AML (including those who progressed from myelodysplastic syndrome (MDS)), prognosis is poor. These patients have been the target of recent clinical development in AML. At ASCO 2016 we will see the pivotal results for a novel chemotherapeutic, Vyxeos™ (CPX-351, Celator Pharmaceuticals), which could transform care for a subset of patients. Vyxeos is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio that was designed to maintain an optimized ratio of the two drugs together to maximize efficacy outcomes.

Celator chose to study Vyxeos in the first-line setting in a subpopulation of patients at higher unmet need, specifically those with secondary AML and/or poor cytogenetics. In this patient population, a Phase III trial (NCT01696084) compared Vyxeos versus 7+3 as first induction therapy. In March 2016, Celator announced that this trial had met the primary endpoint of prolonging overall survival (OS), with a 3.6-month improvement favoring the Vyxeos arm (9.6 months vs. 6.0 months, HR 0.69, p=0.005), and landmark analysis suggested the benefit with Vyxeos was maintained over time. Based on these data, Celator plans to file for regulatory approval in the U.S. and Europe in the third quarter of 2016 and first quarter of 2017, respectively. Abstract 7000, Saturday, June 4, 3:00 p.m.

 

Immunotherapy in head and neck cancer

What discussion of exciting trends would be complete without examination of the PD-1 inhibitors Opdivo™ (nivolumab, Bristol-Myers Squibb/ONO) and Keytruda® (pembrolizumab, Merck)? Since first being approved by the FDA in 2014, these compounds have begun to dominate the market and have been in fierce competition with each other at every step of the way.

In a Clinical Science Symposium titled “Harnessing the Immune System in Head and Neck Cancer: Evolving Standards in Metastatic Disease” (Monday 11:30 a.m. – 1:00 p.m.), a series of abstracts will examine the role of these and similar compounds in patients with squamous cell carcinoma of the head and neck (SCCHN).

First up is Opdivo with updated/reprised data from the Phase III CheckMate 141 trial that compared Opdivo versus investigator’s choice of therapy in patients with SCCHN with tumor progression on or within six months of platinum therapy. Results from this trial showed a significant OS benefit favoring Opdivo (7.5 months vs. 5.1 months, HR 0.70, p=0.0101), which ultimately led to the FDA awarding it Breakthrough Therapy designation in April 2016. These results were presented initially at the 2016 annual meeting of the American Association for Cancer Research (AACR),2 but this reprisal at ASCO will bring the data into view for a much wider audience of clinicians.

Keytruda will follow with a series of abstracts anchored around the first presentation of results from the single-arm KEYNOTE-055 trial that examine efficacy of Keytruda after platinum and Erbitux® (cetuximab, Lilly/Merck KGaA) failure. Results of this study haven’t been reported, but Merck has already filed for approval and the FDA took quick action, setting a priority review PDUFA date of August 9, 2016, by which to act on the application. In the Phase I KEYNOTE-012 study, single-agent Keytruda produced a response rate of 24.8% in a largely third-line or later population,3 and an update on this trial will be reported in this same session at ASCO 2016. Kantar Health will be watching to see whether this level of efficacy can be maintained in the KEYNOTE-055 trial. Also of importance is information on the potential role of the PD-L1 biomarker as a predictor of response to Keytruda in recurrent/metastatic SCCHN, which will be discussed in a third presentation in this session. Biomarkers are a possible point of distinction between the two compounds. Abstracts 6009-6012, Monday, June 6, 11:30 a.m.


Darzalex plus VelDex in patients with relapsed or refractory multiple myeloma (CASTOR)

Darzalex™ (daratumumab, Genmab/Janssen) was recently approved as a first-in-class anti-CD38 monoclonal antibody in fourth-line multiple myeloma. This approval was based on the results of the pivotal Phase II SIRIUS study, in which single-agent Darzalex resulted in an objective response rate (ORR) of 29.2% in patients who had received a median of five prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.4 Although the SIRIUS trial offered an important opportunity to gain accelerated approval for Darzalex, the true opportunity lies in earlier lines of therapy. As such, Janssen initiated two Phase III studies of Darzalex in combination with the standard of care in second-line myeloma. The first of these studies to report is CASTOR, which compares the combination of Darzalex, Velcade® (bortezomib, Millennium/Janssen) and dexamethasone (VelDex) versus VelDex in patients previously treated with at least one prior line of therapy. In March 2016, Genmab announced that the trial met the primary endpoint of improving progression-free survival (PFS) in an interim analysis (p≤0.0001), prompting the independent data monitoring committee to recommend early stoppage of the trial.

Although it is highly treatable, multiple myeloma is rarely curable, and patients often become resistant to therapy. As such, data from this trial would be very well received if the combination provides a meaningful improvement in time to relapse or minimizes resistance. Darzalex itself is still very new to the market, and as the first human anti-CD38 monoclonal antibody it has the potential to change the landscape. In the second-line setting, Darzalex will be competing directly with Empliciti™ (elotuzumab, AbbVie/Bristol-Myers Squibb) and Kyprolis® (carfilzomib, Amgen), both of which were approved in the past year as part of triplet regimens (both in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone, RevDex). Both regimens produced very strong PFS benefits in comparison with doublet therapy (RevDex). Key for Darzalex will be demonstrating a level of PFS benefit that is at least comparable to that observed with the Empliciti or Kyprolis triplets, and/or other safety or efficacy differentiators, to overcome the fact that it will be third to market in this setting. Abstract LBA4, Sunday, June 5, 3:10 p.m.

 

Kadcyla + Perjeta as neoadjuvant therapy in early-stage HER2-positive breast cancer (KRISTINE)

In the treatment of HER2+ breast cancer, Genentech/Roche compounds have become the standards of care in most treatment settings – Herceptin® (trastuzumab) in the adjuvant setting, the combination of Herceptin plus Perjeta® (pertuzumab) in first-line metastatic disease, and Kadcyla® (ado-trastuzumab emtansine) in second-line metastatic disease.1 Most recently, Perjeta became part of the first regimen to be FDA-approved for use in the neoadjuvant setting based on a significant improvement in pathologic complete response rate (pCR) for the combination of Perjeta + Herceptin + docetaxel. Roche also has been seeking to advance the development of Kadcyla beyond the relapsed/refractory setting, with several Phase III trials initiated in various settings. The highly anticipated MARIANNE trial was somewhat of a shocking disappointment in December 2014 when it failed to show a benefit for the use of Kadcyla + Perjeta in first-line metastatic disease.5 Similar studies continue in early-stage disease and initial results from the first of these trials, KRISTINE, will be reported at ASCO 2016. KRISTINE (NCT02131064) evaluates the efficacy of Kadcyla + Perjeta in comparison with Herceptin + Perjeta + chemotherapy in the peri-operative setting, with patients receiving six cycles of neoadjuvant (pre-operative) treatment followed by surgery; following surgery, patients will receive adjuvant Kadcyla + Perjeta versus Herceptin + Perjeta.

Results of this study have not been announced publicly, so it’s unknown whether the presentation at ASCO will be positive or negative. The MARIANNE trial in first-line metastatic disease showed no difference in PFS, OS or ORR among the three study arms. However, a Phase Ib/IIa open label study evaluated Kadcyla and docetaxel with or without the addition of Perjeta as neoadjuvant therapy in 70 previously untreated HER2+ locally advanced breast cancer patients (NCT00934856). The pCR rate was relatively similar in patients who received the Perjeta/Kadcyla/docetaxel regimen (60.6%) compared with those who received Kadcyla/docetaxel (56.8%).6 Although the pCR rates in these two arms were similar, both are notably higher than the pCR rate upon which Perjeta + Herceptin + docetaxel was FDA-approved in the neoadjuvant setting (39%).7 Importantly, the Kadcyla + Perjeta combination demonstrated improved safety and quality of life in the MARIANNE trial. The tolerability of this combination will be a key to watch in the KRISTINE trial, as safety takes on even greater importance in potentially curative early-stage disease. Additionally, the KRISTINE trial will be important to watch in terms of potential for short-term advancement of Kadcyla, as well as possible foreshadowing of results to come from the adjuvant KATHERINE and KAITLIN trials. Abstract 500, Monday, June 6, 1:15 p.m.

tbl1_Kantar_Top Abstracts_5.16

References:

  1. Kantar Health, CancerMPact® Treatment Architecture, accessed from www.cancermpact.com, May 2, 2016.
  2. Gillison ML, Blumenschein G, Fayette J, et al.; “Nivolumab (nivo) vs investigator’s choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141”, [Abstract CT099]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract CT099.
  3. Seiwert TY, Haddad RI, Gupta S, et al.; “Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort;” J Clin Oncol 33, 2015 (suppl; abstr LBA6008).
  4. Reeder CB, Gornet MK, Habermann TM, et al.; “A Phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma;” Leukemia, 25(2): 342-347, 2011.
  5. Ellis PA, Barrios CH, Eiermann W, et al.; “Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study;” J Clin Oncol 33, 2015 (suppl; abstr 507).
  6. Martin M, Dewar J, Albanell J, et al., “Neoadjuvant trastuzumab emtansine and docetaxel, with or without pertuzumab, in patients with HER2-positive early-stage breast cancer: Results from a phase 1b/2a study,” Proc San Antonio Breast Canc Symp, Abstract P4-12-07, 2013.
  7. Perjeta® (pertuzumab) FDA-approved label. Accessed at www.perjeta.com, May 2, 2016.

June 02, 2015 - 03:06 pm Posted in ASCO Conference Coverage comments0 Comments

By Mara Jeffress, Ph.D., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

The number of agents available to treat relapsed/refractory myeloma has expanded rapidly over the past three years, with the launch of next-generation proteasome inhibitor Kyprolis® (carfilzomib, Onyx /Amgen, accelerated FDA approval July 2012) and the next-generation immunomodulator Pomalyst® (pomalidomide, Celgene, FDA approved February 2013) as monotherapies, and the HDAC inhibitor Farydak® (panobinostat, Novartis, accelerated FDA approval February 2015) for use in combination with bortezomib + dexamethasone (VelDex). These three agents add to the long-established standards of care, Velcade® (bortezomib, Millennium/Takeda) and Revlimid® (lenalidomide, Celgene), which are used in both newly diagnosed and relapsed/refractory patients. Pivotal data for Kyprolis and two new agents ― elotuzumab (AbbVie/Bristol-Myers Squibb) and daratumumab (Genmab/Janssen) ― were presented on Tuesday at the Myeloma Oral Session of the American Society of Clinical Oncology (ASCO) annual meeting.

Based on the results of a large Phase II program, Kyprolis was granted FDA accelerated approval as a monotherapy for myeloma patients who have received prior therapy with an immunomodulatory agent and proteasome inhibitor. It is now the most commonly used third-line agent, used in one-third of patients.1 As a second-generation proteasome inhibitor, the ability of Kyprolis to gain use in earlier lines of therapy will hinge on demonstrating benefit in comparison with the entrenched first-generation proteasome inhibitor, Velcade. The Phase III ENDEAVOR trial compared Kyprolis (at a dose of 56 mg/m2, twice the currently approved monotherapy dose of 27 mg/m2) plus dexamethasone (KypDex) versus VelDex in 929 patients who have received one to three prior lines of therapy (50% were second-line, 33% were third-line and 17% were fourth-line). Progression-free survival (PFS) was significantly improved, with the KypDex arm doubling PFS at the median compared to VelDex (median PFS 18.7 versus 9.4 months, HR=0.53, p< 0.0001).2 Overall survival (OS) data were immature; however, a slight trend to benefit was suggested in the data presented (HR=0.79, p=0.66). Overall response rates (ORR) also favored Kyprolis: 77% versus 63% (p< 0.0001); 54% versus 29% had a very good partial response or better, and 13% versus 6% of patients had a complete response. Responses were robust even in patients treated with prior Velcade. Treatment discontinuation (14.0% vs. 15.7%) and on study death (3.9% vs. 3.4%) due to an adverse event (AE) occurred at similar frequencies in each arm. Grade 3/4 hypertension (8.9% vs. 2.6%), dyspnea (5.6% vs. 2.2%), cardiac failure (4.8% vs. 1.8%) and acute renal failure (4.1% vs. 2.6%) were all increased in the KypDex arm. Considering the fact that patients in this trial were receiving double the approved monotherapy dose, the AEs perhaps aren’t unexpected, although they are still concerning when considering the use of this regimen in the general population of myeloma patients outside of a highly selected clinical trial. These increased toxicities were balanced by a significant decrease in Grade 2 or higher peripheral neuropathy (6.3% vs. 32.0%, p< .0001), which is all the more encouraging considering that the majority (79%) of patients in the control arm received subcutaneous (SC) Velcade, which has lower rates of neuropathy compared to the intravenous (IV) formulation.

The near doubling of PFS over VelDex will establish KypDex as a new standard of care, especially if OS data is positive. The positive results from ENDEAVOR should only serve to strengthen Kyprolis’ share in third-line and help it gain share in second-line, where VelDex is currently utilized in one-third of patients.1 The positive results of ENDEAVOR come just six months after another positive Phase III trial for Kyprolis – the ASPIRE trial, which showed that patients receiving Kyprolis combined with lenalidomide + dexamethasone (RevDex) had a median PFS of 26.3 months compared to a median PFS of 17.6 months for patients treated with RevDex alone (HR=0.69; p=0.0001).3 Together, these two trials raise questions about where Kyprolis will fit in the treatment paradigm – as a doublet or a triplet, and in which line of therapy?

While Kyprolis, at least in ENDEAVOR, is challenging Velcade head-to-head, elotuzumab is choosing to combine with one of the current standard-of-care treatment regimens, RevDex. Elotuzumab is an anti-SLAMF7 monoclonal antibody that has FDA Breakthrough Therapy Designation for relapsed/refractory multiple myeloma and is being studied in two Phase III trials, both in combination with RevDex, in the front-line and relapsed/refractory settings. In the relapsed setting, the results of the ELOQUENT-2 trial compared elotuzumab in combination with RevDex versus RevDex alone in 646 patients who had received a median of two prior therapies, including Velcade (70%), thalidomide (48%) and Revlimid (6%). Revlimid-refractory patients were excluded from enrollment. Elotuzumab given with RevDex extended PFS by a median of 4.5 months compared with RevDex alone (median PFS 19.4 vs. 14.9 months, HR = 0.70, p = 0.0004). In addition, one-year PFS was 68% versus 57% and two-year PFS was 41% versus 27%. ORR also favored the addition of elotuzumab (79% vs. 66%, p = 0.0002).4 OS is still immature and was not reported, but the presenter, Dr. Lonial, suggested the results, which will be available in the fourth quarter of 2015, were trending toward the positive. There were no significant increases in toxicity except for Grade 3/4 lymphopenia (77% vs. 49%) and increased incidence of Grade 1-3 infusion reactions (10% vs. 0%); Grade 3/4 neutropenia was lower in the elotuzumab arm (34% vs. 44%). A large number of high-risk patients were enrolled in the trial (32% del17p and 10% t(4;14)), and subgroup analysis showed that PFS was robust even in these subgroups (HR=0.65 for del17p and HR=0.53 for t(4;14)). While important to understand that the regimen provides benefit in these subsets, it does create difficulties for cross-trial comparisons.

Acknowledging the trial demographic differences, a comparison of ELOQUENT-2 with outcomes for KypDex and Kyprolis + RevDex suggests that elotuzumab + RevDex might provide a comparable median PFS and ORR as is achieved with KypDex (although the Hazard Ratio was better for KypDex), and inferior median PFS and ORR compared to KypRevDex (comparison is difficult here as fewer patients (12.6%) in ASPIRE were high-risk, which may have boosted the mPFS); however, the AE profile appears most benign for elotuzumab in combination with RevDex. A key advantage of elotuzumab is its novel mechanism of action and its combinability with other agents due to its relative mild toxicity profile. While these advantages may give elotuzumab a strong positioning stance in newly diagnosed patients, competitive pressures are stronger in relapsed myeloma. Most significant may be the changing backbone of care across the lines of therapy (choice of immunomodulator or proteasome inhibitor or both), which may leave fewer opportunities for use of elotuzumab if its approval in the relapsed/refractory setting is tied to the RevDex combination.

Elotuzumab is aiming to be the first monoclonal antibody used to treat multiple myeloma. Competition will come quickly from another antibody known as daratumumab. Daratumumab is a human monoclonal antibody directed against CD38, which is highly expressed on the surface of multiple myeloma cells. Daratumumab has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Based on promising early data, the FDA granted Breakthrough Therapy Status to daratumumab for treatment of double-refractory multiple myeloma.

Daratumumab, at least initially, is taking a slightly different development tactic than either Kyprolis or elotuzumab and is hoping to enter the myeloma market initially by targeting fourth-line or later patients.5 An open-label, two-part Phase II study (Sirius, MMY2002, NCT01985126) evaluated daratumumab monotherapy in its FDA breakthrough therapy designation population: double-refractory myeloma patients with at least three prior lines of therapy. In part 1, 34 patients were randomized to daratumumab 8 mg/kg (n = 18) or 16 mg/kg (n = 16) to determine the most effective dose. In part 2, 90 additional patients were given the 16 mg/kg dose. Data for 106 heavily pretreated (median five prior lines, including 95% double refractory and 66% refractory to three of four approved agents (Revlimid, Velcade, Pomalyst and/or Kyprolis)) patients were reported. After a median follow-up of 9.3 months, 29% of patients responded to daratumumab, including three complete responses, 10 very good partial responses, and 18 partial responses. Responses to daratumumab were rapid and durable, lasting on average 7.4 months. Response was consistent across all subgroups including the most refractory patients. Median PFS was 3.7 months. Median OS has not been reached, and the estimated one-year OS rate is 65%, which is remarkable in such a refractory population. Common all-grade AE (≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%) and cough (20.8%). Infusion-related reactions were common (43%) but mainly Grade 1/2 (5% Grade 3; 0% Grade 4). J&J intends to seek accelerated approval for daratumumab later this year6 and already has plans to enter the ranks of emerging triplet therapies in myeloma, by initiating two Phase III trials in relapsed/refractory patients combining daratumumab with VelDex (NCT02136134) or with RevDex (NCT02076009). The discussant, Dr. Lentzsch, enthusiastically reviewed the Phase I/II data showing that daratumumab plus RevDex had an impressive 87% ORR with responses that deepened over time.

Given the increasingly crowded relapsed/refractory setting, companies that plan to bring more agents to multiple myeloma will need to go head-to-head against or combine with RevDex, VelDex, KypDex or the various established and emerging triplet regimens. As we have seen in other crowded markets such as renal cell carcinoma, even existing approved agents may be forced into head-to-head trials to establish dominance and win a significant portion of the market. As of now, there is no clear winner, and the influx of new agents will only confuse matters more with the lack of understanding of whether triplets are better than doublets, if quadruplets are better than triplets (this is sure to be explored in the near future), which regimen is superior and how to sequence the drugs. Furthermore, across all scenarios also exists the question of cost of care. Can the market (and patients) afford combination therapies that continue to push the boundaries of affordability? The price may be justified if the new combination therapies can provide a long-term survival benefit, but for now the regimens reported here have only firmly established a PFS benefit.

References:

1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.

2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. J Clin Oncol. 2015;33(suppl; abstr 8509)

3. Stuart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. NEJM, 372(2): 142-52, 2015.

4. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(suppl; abstr 8508)

5. Lonial S, Weiss BM, Usmani SZ et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33(suppl; abstr LBA8512)

6. Johnson & Johnson press release, May 20, 2015.

June 02, 2015 - 02:06 pm Posted in ASCO Conference Coverage comments0 Comments

By Arnold DuBell, Ph.D., M.B.A., Consultant; Elizabeth Clarke, Ph.D., M.P.H., Analyst; Stephanie Hawthorne, Ph.D., Senior Director; Len Kusdra, Ph.D., Analyst; and Gregory Wolfe, Ph.D., Senior Consultant – Clinical & Scientific Assessment, Kantar Health

Immunotherapy has dominated the conversation in oncology for the past several years, and the excitement still hasn’t waned at all — in fact, it continues to grow. New drugs have entered development in this space, new mechanisms of action have emerged, and new tumor types have become the focus of our attention. We have previously seen various levels of evidence to support the activity of checkpoint inhibitors in melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, breast cancer, gastric cancer, head and neck cancer and Hodgkin’s lymphoma. At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), we observed first reports of the activity of several PD-1 and PD-L1 inhibitors in multiple new tumor indications, adding to the growing body of evidence that suggests immunotherapy is closely approaching panacea status.

Hepatocellular carcinoma

Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) was studied in a global Phase I/II trial in patients with advanced hepatocellular carcinoma (HCC).1 This was a dose-escalation study, and it also stratified patients according to their hepatitis B/C viral (HBV, HCV) infection status (uninfected vs. HCV-infected vs. HBV-infected). The majority of patients (75%) had received prior systemic therapy for their disease, with most (68%) having received prior Nexavar® (sorafenib, Onyx/ Amgen/Bayer). At this interim analysis of 42 evaluable patients, single-agent Opdivo produced a 19% objective response rate (ORR; which was measured across all dose cohorts), including two patients (5%) with a complete response; an additional 48% of patients had stable disease. Responses were seen in all patient cohorts, but the response rate was higher in those with HCV infections (36%). It was postulated that perhaps patients with higher viral load/disease burden are more sensitive to PD-1 inhibition and speculated that HCV T-cells may naturally express higher levels of PD-L1, making them more sensitive to PD-1 inhibition; both of these observations are very preliminary in nature, however, and need more data to fully understand whether there is a correlation with activity and, if so, why. The duration of responses were very encouraging (out to one year in some patients) and the one-year overall survival (OS) rate was 62% — unheard of in metastatic, relapsed HCC! These are exciting data in a tumor of very high unmet need, and we’re looking forward to following this trial for the final results and monitor for future clinical development in this indication.

Esophageal

There has been little development of targeted therapies for esophageal cancer, making it a tumor of small incidence but large unmet need. Immunotherapy agents have already shown promise in gastric and gastroesophageal junction adenocarcinoma, so it was nice to see a presentation describing the first data for this class in patients with metastatic esophageal cancer. An expansion cohort of the Phase Ib KEYNOTE-028 trial enrolled 23 patients with primarily PD-L1-positive, heavily pretreated esophageal cancer (a few patients had gastroesophageal carcinoma).1 Treatment with single-agent Keytruda® (pembrolizumab, Merck & Co.) was associated with a 30.4% partial response rate (29.4% in the 17 patients with squamous cell carcinoma and 40.0% for the five patients with adenocarcinoma). Responses are very durable, with an average duration of response of 40 weeks. More than half of patients showed some degree of tumor shrinkage. These are excellent outcomes, especially considering that a 30% response rate isn’t much different than that usually seen in the first-line setting for gastroesophageal cancer. However, the discussant, Dr. Fuchs, emphasized slight caution due to the lack of central review in this trial. Similar to other trials for Keytruda, adverse events (AEs) were very limited, with only four patients (17.4%) experiencing Grade 3 toxicities. During the discussion, Dr. Fuchs hypothesized on why these patients seemed to respond so well to Keytruda. Although the patients with the Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI)-positive2 adenocarcinoma subtypes might be responding to increased immune activity due to association of these subtypes with increased PD-L1 expression, the responses in patients with squamous cell carcinoma may be associated with the high degree of DNA focal copy number alterations. Further research is warranted to evaluate these hypotheses as well as confirm the encouraging activity of Keytruda in these patients.

Ovarian Cancer

Today results were presented from two separate Phase Ib studies that are evaluating safety and efficacy of PD-1 checkpoint inhibitors in patients with relapsed/refractory ovarian cancer. In the first of the two trials,3 75 heavily pretreated ovarian cancer patients enrolled in an expansion cohort were treated with the PD-L1 inhibitor avelumab (Merck KGaA/Pfizer). Patients were not selected based on PD-L1 status. There were no complete responses, and eight patients achieved partial responses for an ORR of 10.7%. Stable disease was the best response in 33 patients, for a clinical benefit rate of 54.7%. Responses were ongoing in five of eight patients, and the median duration of response was nine weeks. Grade 3/4 adverse events were reported in six patients (8%), and the most common treatment-related AEs of any grade included fatigue (16.0%), chills (12.0%), nausea (10.7%) and diarrhea (10.7%). The author noted that a Phase III trial of avelumab is currently being planned. The second presentation reported results from the ovarian cancer cohort (n=26) of the Phase 1b KEYNOTE-028 trial.4 Heavily pretreated, PD-L1-positive patients were enrolled in KEYNOTE-028 and received the anti-PD-1 antibody Keytruda, and they were treated for 24 months or until disease progression. The ORR was 11.5% and included one complete response and two partial responses. Another six patients achieved stable disease for a disease-control rate of 34.6%. Median duration of response was not reached. Grade 3/4 AEs were reported in 3.8% of the patients, and the most common treatment-related AEs included arthralgia (23.1%), diarrhea (11.5%) and nausea (11.5%). The authors are further analyzing their data to discern whether there is a relationship between PD-L1 expression and activity. These two studies demonstrate that both anti-PD-1 and anti-PD-L1 antibodies are well-tolerated and active in heavily pretreated ovarian cancer patients. Interestingly, the ORR was similar between the two trials; therefore, as with other indications, physicians may need to wait for follow-up data to determine the ultimate choice of immunotherapy option.

Glioblastoma

Another example where immunotherapies may make an impact is in recurrent glioblastoma multiforme (GBM), which has a poor prognosis when treated with current therapies and thus represents a considerable unmet need. PD-L1 expression has been associated with high-grade but not low-grade gliomas.5 Also, antitumor activity using a non-commercial anti-PD-1 monoclonal antibody was observed in mouse glioma models.6 Given this preliminary data, Bristol-Myers Squibb (BMS) initiated the Phase III CheckMate-143 trial, which will randomize patients to Opdivo or Avastin® (bevacizumab, Genentech/Roche/Chugai) after progression following surgical resection, radiation and temozolomide. The design of CheckMate-143 included a safety run-in phase evaluating Opdivo with or without Yervoy® (ipilimumab, BMS), which reportedly helped influence the Phase III trial design; some of this data from 20 patients were presented in a poster session at ASCO 2015.7 Note that the arms containing Yervoy were included based on activity observed for Yervoy in patients with melanoma and brain metastases.8 In the data just presented, treatment-related serious AEs occurred in two patients in the monotherapy arm and seven patients treated with the combination. Moreover, as might be expected, the combination regimen had more treatment-related discontinuations (40% vs. 0%). With this said, Opdivo monotherapy was very well tolerated. Opdivo monotherapy was associated with a 10% partial response (PR) rate and a 50% clinical benefit rate; six- and nine-month OS rates were 70% and 60%, respectively. In contrast, Opdivo plus Yervoy was associated with no PRs and a 40% stable disease rate; six- and nine-month OS rates were 80% and 60%, respectively. Given this data, Opdivo monotherapy was chosen to be evaluated in the Phase III trial initiated last year. With the limited options currently available for GBM patients, there should be a high level of enthusiasm to quickly see the outcome from this trial.

Small Cell Lung Cancer

Checkpoint inhibitors are active in other thoracic tumors. Opdivo is already approved for use in non-small cell lung cancer (NSCLC) patients with squamous histology and recently excited ASCO attendees with the CheckMate-057 data in patients with non-squamous histology. Keytruda also showed strong promise in both NSCLC in the KEYNOTE-001 trial and malignant pleural mesothelioma in an expansion cohort of the Phase Ib KEYNOTE-028 trial. Given the level of competition between the two molecules in these other thoracic tumors, it is not surprising to see data for both agents in small cell lung cancer (SCLC). A different cohort from Keynote-028 examined the safety and preliminary efficacy of Keytruda in 20 patients with PD-L1-positive relapsed SCLC.9 The toxicity profile was mild, with 10% of patients having Grade 3 or greater AEs; one fatality occurred due to Grade 5 colitis. There was promising evidence of efficacy, with seven (35%) evaluable patients achieving a partial response. Median time to response was 8.6 weeks, with six of seven responses ongoing at the time of data cutoff; one patient has exhibited a response of at least 32 weeks. Opdivo was evaluated in the CheckMate-032 trial, a Phase I/II trial randomizing 90 heavily pretreated SCLC patients to Opdivo with or without Yervoy.10 The combination was evaluated at two dose levels: Yervoy dosed at 1 mg/kg or 3 mg/kg. The most common Grade 3/4 side effects in patients receiving Opdivo plus Yervoy included diarrhea (8.5%), increase in lipase (6.4%), rash (4.3%) and vomiting (4.3%); the total incidence of Grade 3/4 toxicities was 15% for the monotherapy and 34% for the combinations. The initial ORR for Opdivo monotherapy was 18% (CR 0%) and for both combinations was 17% (CR 2%). The ORR for the combination increased with continued treatment, as seven patients with initial stable disease were upgraded to confirmed partial responses, resulting in an ORR of 32.6%. Subgroup analysis showed that this level of response was found in both platinum-sensitive and platinum-resistant patients. Median duration of response was 6.9 months for the combination and was not reported for the monotherapy. Median OS was 4.4 months for Opdivo monotherapy and 8.2 months for the combination. Neither trial showed evidence of a linkage between increased PD-L1 expression and activity. Although Keytruda showed a higher level of activity than Opdivo monotherapy (35% versus 18%), the numbers of patients and the inability at this stage to assess how similar the patient populations are will force physicians to wait for further data in this indication to help them make choices as to which immunotherapy to offer their SCLC patients.

Colorectal

In the original Phase I trial for Opdivo presented at ASCO 2012,11 no responses were observed among 19 patients with colorectal cancer (CRC). At ASCO 2015, however, data presented from a new Phase I trial suggests a subset of these patients may actually benefit from PD-1 inhibition. In a multicohort Phase II trial, patients with pretreated CRC were enrolled into two cohorts – those with tumors proficient for mismatch repair (MMR; n=25, n=25 evaluable) and those with MMR-deficient tumors (n=25; n=13 evaluable); a third cohort enrolled patients with MMR-deficient non-colorectal pretreated solid tumors (n=21; n=10 evaluable). Activity was strikingly different among these cohorts of patients following treatment with Keytruda. The ORR was 62% in MMR-deficient CRC patients and 60% ORR in MMR-deficient non-colorectal cancers, but the ORR was 0% in patients with MMR-proficient CRC. The difference can’t be blamed on the depth of response, because disease control including stable disease was equally different: 92% in MMR-deficient CRC, 70% in MMR-deficient non-colorectal cancers, and only 16% in MMR-proficient CRC. Progression-free survival and OS were also longer in patients with MMR-deficient CRC or other cancer compared to patients with CRC-proficient tumors. Although the sample sizes of MMR-deficient CRC and MMR-deficient non-CRC cohorts were small, and there was a slight imbalance in patient demographics between the cohorts (MMR-proficient CRC patients were older and slightly more pretreated), the degree of differential efficacy seems large enough to suggest the correlations may be real. Additional analysis shows that MMR-deficient tumors have greater density of invasive CD8+ T-cells, greater density of PD-L1-positive invasive CD8+ T-cells, and more somatic mutations per tumor than MMR-proficient tumors. Together, these data point to a possible mechanistic explanation for the differential activity of Keytruda, wherein higher tumor mutational burden leads to greater immune system recognition and tumor infiltration, leading to improved activity of PD-1 inhibitors.

This theory explains the exquisite activity of checkpoint inhibitors that has been observed in melanoma, NSCLC, bladder cancer, SCLC, gastric cancer, esophageal cancer and head and neck cancer: These tumors have the highest somatic mutational burden according to data from the Cancer Genome Project.12 Although mutational load is unlikely to be the only factor that influences likelihood of response to checkpoint blockade, new data from ASCO 2015 suggest it certainly plays a role and may need to be considered for future development plans and eventually patient selection across a number of solid tumor types.

References:

1. El-Khouery AB, Melero I, Crocenzi TS, et al.; “Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040;” J Clin Oncol 33, 2015 (suppl; abstr LBA101).

2. MSI: microsatellite instability; EBV: Epstein-Barr Virus

3. Disis ML, Patel MR, Pant S, et al.; “Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory: a phase Ib open label expansion trial;” J Clin Oncol, 33 (suppl., abstr 5509), 2015.

4. Varga A, Piha-Paul SA, Ott PA, et al.; “Antitumor activity and safety of pembrolizumab in patients with PD-L1 positive ovarian cancer: interim results for a phase 1b study;” J Clin Oncol, 33 (suppl., abstr 5510), 2015

5. Yao Y, Tao R, Wang X, et al.; “B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells;” Neuro Oncol, 11:757–766, 2009.

6. Zeng J, See AP, Phallen J, et al.; Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas;” Int J Radiat Oncol Biol Phys, 86: 343-349, 2013.

7. Sampson JH, Vlahovic G, Sahebjam S, et al.; “Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CheckMate-143; J Clin Oncol, 33 (15_supp), Abst 3010, 2015.

8. Margolin K, Ernstoff MS, Hamid O, et al.; “Ipilimumab in patients with melanoma and brain metastases: an open-label phase 2 trial;” Lancet Oncol, 13:459-465.

9. Ott PA, Fernandez MEE, Hiret S, et al.; “Pembrolizumab in patients with extensive-stage small cell lung cancer: Preliminary safety and efficacy results from KEYNOTE-028;” J Clin Oncol. 33 (suppl. Abstr 7502), 2015.

10. Antonio SJ, Bendell JC, Taylor MH, et al.; “Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer: CA209-032;” J Clin Oncol. 33 (suppl. Abstr 7503), 2015.

11. Le D, Uram J, Wang H, et al.; “PD-1 blockade in tumors with mismatch repair deficiency;” J Clin Oncol 33, 2015 (suppl; abstr LBA100).

12. Alexandrov LB, Nik-Zainal S, Wedge DC, et al.; “Signatures of mutational processes in human cancer;” Nature 2013, 500: 415-421.

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