The OBR Blog

December 12, 2014 - 11:12 am Posted in SABCS Conference Coverage comments0 Comments

Immunotherapy is all the rage these days in oncology, and there is particular interest in those agents that target programmed death 1 (PD-1) and its ligand, PD-L1. In several solid tumors (and hematologic tumors as we saw at ASH last week) there is a race to market for this class of compounds by multiple competitors. Data presented in the past two years in melanoma have been impressive and have led to approvals of Keytruda® (pembrolizumab, Merck; U.S. FDA approval September 2014) and Opdivo® (nivolumab, BMS/Ono; Japanese MHLW approval July 2014 ) in advanced/metastatic disease and will likely lead to approvals in other indications in the near future (non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are nearest term). Robust research in this area continues to push into additional indications, including breast cancer. In general, breast cancer is seen as less responsive to immunotherapy, and there has been some skepticism about the ability of immunotherapy to deliver.  In particular, mutant proteins that serve as “neo-antigens” to the immune system are very low in breast cancer compared to other solid tumors.1 However, high levels of tumor-infiltrating lymphocytes (TILs) do seem to predict pathological complete response (pCR) in breast cancer patients,2 suggesting that the immune system is an important factor in the fight against this disease.

The question as to whether or not immunotherapy can be successful in breast cancer began to be answered Wednesday, December 10, 2014, at the San Antonio Breast Cancer Symposium (SABCS) with two presentations demonstrating early signals of activity for PD-1 and PD-L1 inhibitors in triple-negative breast cancer (TNBC) patients. Wednesday’s oral general session was the venue for the first results of Keytruda in 32 advanced TNBC patients treated in the ongoing Phase Ib KEYNOTE-012 study.3 The trial enrolled heavily pretreated patients (47% had three or more prior lines of chemotherapy) with PD-L1+ disease and treated them with pembrolizumab monotherapy at 10 mg/kg every two weeks. In 27 evaluable patients, the objective response rate (ORR) was 18.5% (1 CR, 4 PR) and median duration of response (DoR) was not reached (range, 15-40+ weeks), with three of five responders remaining on therapy for 11+ months. Adverse events (AEs) were mostly Grade 1/2, including fatigue (18.8%), arthralgia (18.8%), myalgia (15.6%) and nausea (15.6%). Grade 3/4 treatment-related AEs occurred in four patients – anemia, headache, meningitis aseptic, decreased blood fibrinogen and pyrexia – with two patients discontinuing drug due to AEs. There was also one death due to disseminated intravascular coagulation (DIC). Based on this encouraging data, the presenter, Dr. Nanda, disclosed Merck’s plans to start a Phase II trial in TNBC in the first half of 2015 and hinted during the Q&A at plans to pursue the other breast cancer subtypes, such as HER2+ patients, who may also be susceptible to immunotherapy. Small trials, such as PANACEA (NCT02129556), which will examine Keytruda in combination with Herceptin® (trastuzumab, Genentech/Roche/Chugai) in advanced Herceptin-resistant HER2+ breast cancer, should start recruiting soon.

Also on Wednesday, there was a poster presentation of data from a small cohort of 12 patients in the ongoing Phase Ia dose-escalation study of MPDL3280A (anti PD-L1, Genentech/Roche/Chugai), which evaluates doses of 0.3-20 mg/kg every three weeks in previously treated patients with advanced, PD-L1+ TNBC. 4 In nine evaluable patients, ORR was 33% (1 CR, 2 PR); however, there were an additional two responders who were initially pseudo-progressors and were not included in the calculated ORR. Grade 3/4 treatment-related AEs occurred in only one patient, and no dose-limiting toxicities occurred. Further evaluation of MPDL3280A is ongoing in both PD-L1-positive and -negative TNBC patients (NCT01375842).

In both studies, response was measured by RECIST criteria, not immune-related-response criteria that take into account that some patients on immunotherapy initially progress before responding. Had these alternative criteria been used, perhaps the ORR would have been higher. Despite this, the ORR reported in these two studies (19% and 33%) are similar to the ORR reported for PD-1 / PD-L1 inhibitors in other solid tumors ( 31%-34% in melanoma,5,6 17%-21% in NSCLC,7,8,9 20% in RCC and head and neck10,11). Perhaps more important than the response rate is the extent to which the PD-1/PD-L1 inhibitors are able to slow the progression of disease and prolong survival. The duration of response data for Keytruda is the only piece of data that is yet available to guide toward an answer to this question in breast cancer, but it is a promising start – metastatic TNBC has a notoriously poor prognosis, and to see duration of response nearing one year in later lines of therapy is very encouraging. What will be more encouraging is to see an OS benefit extending beyond just those patients who achieve an objective response, as we have come to expect from immunotherapies in many tumors.

Despite the small cohort of patients and limited data, discussant Dr. Disis was very positive on the results and called for researchers to move ahead and consider combination trials in breast cancer. This is a bit of a departure from typical breast cancer treatment strategies, which tend to focus on sequential monotherapies rather than combination regimens. The immunotherapy field is beginning to explore combination approaches in other solid tumors, so extending that idea to breast cancer isn’t novel. The approach Keytruda is taking (combining with Herceptin) is somewhat expected in breast cancer, although is limited to HER2+ patients. In TNBC patients, however, no targeted therapy options are yet developed with which to combine; chemotherapy thus becomes the de facto combination partner (Celgene is conducting a Phase I trial that includes study of Opdivo with Abraxane® (nab-paclitaxel) in second-line HER2-negative disease (NCT02309177)), although this approach negates the low-toxicity advantage that immunotherapy is meant to afford.  

Breast cancer is the most commonly diagnosed cancer in the U.S. and Europe and is the second most commonly diagnosed cancer globally. Given the large number of patients involved, it is somewhat surprising that the checkpoint inhibitors haven’t been more widely developed in this disease. Perhaps higher unmet need drove early development of PD-1/PD-L1 inhibitors toward other malignancies, but the tides may now be shifting. It seems the immunotherapy wave has finally hit the shores of the breast cancer landscape.

References: 

  1. Disis M., Discussant Oral Session 1, SABCS 2014
  2. Loi S., Educational Session: Introduction to Immunotherapy, SABCS 2014
  3. Nanda R., Abstract S1-09, SABCS 2014
  4. Emens L.A., Abstract PD1-06, SABCS 2014
  5. Ribas, Abstract LBA9000, ASCO 2014
  6. Weber, Abstract LBA3, ESMO 2014
  7. Brahmer, Abstract 8030, ASCO 2013
  8. Rizvi, Abstract 8007, ASCO 2014
  9. Spigel, Abstract 8008, ASCO 2013
  10. Motzer, Abstract 5009, ASCO 2014
  11. Seiwert, Abstract 6011, ASCO 2014

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

December 09, 2014 - 09:12 am Posted in ASH Conference Coverage comments0 Comments

Immune checkpoints in the Programmed Death-1 (PD-1) pathway have critical roles in balancing the co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T‑cell responses. PD-1 is a key immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand (PD-L1) results in suppression of the immune response, and tumor cells can manipulate this critical pathway to elude attack by tumor-infiltrating T-cells.

The two front-runners for this class are Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals). Opdivo holds the title of being the first PD-1 inhibitor to gain regulatory approval when it was approved in Japan in July 2014 for malignant melanoma, while in September 2014 Keytruda became the first PD-1 inhibitor to gain FDA approval (accelerated approval for advanced and unresectable malignant melanoma). Both are currently in development in a number of other solid tumors and now are making a foray into the hematologic space. Both companies released the first-reported clinical results in hematologic malignancies in the same oral presentation session on Sunday, Dec. 8, 2014 at the 2014 American Society of Hematology (ASH) conference.

Unlike solid tumors, in which data has demonstrated strong efficacy for this class in numerous abstracts across multiple tumor types, studies in the hematologic malignancies are still scarce (“disappointingly only four presentations at the 2014 ASH meeting” as elegantly expressed by Dr. Levy in his commentary presentation during a full house Sunday special session on Immune Checkpoint Blockade in Lymphoma).

Opdivo has two stories to tell from its Phase I trial in hematologic malignancies

A Phase I study of Opdivo enrolled a total of 105 patients with relapsed/refractory hematologic malignancies. This trial supported two presentations: one focusing on results from the cohort of 23 patients with relapsed/refractory Hodgkin’s lymphoma1 and the second discussing the remaining 82 patients with other relapsed/refractory lymphoma malignancies (B-cell lymphoma, T-cell lymphoma and multiple myeloma.)2 Safety and tolerability were the primary endpoints, and best overall response, duration of response, progression-free survival (PFS) and biomarker studies were secondary endpoints.

Story One: High overall response rates (87%) in heavily pre-treated relapsed or refractory Hodgkin’s lymphoma1,3

Classical Hodgkin’s lymphoma (cHL) is unique, with Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies have suggested that Hodgkin’s RS cells may have developed mechanisms to exploit the PD-1 pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that correlates with elevated expression of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. The rationale behind this study is that Opdivo may confer antitumor activity in patients with relapsed or refractory (R/R) cHL who have elevated PD-L1 expression. The FDA granted nivolumab Breakthrough Therapy Status for Hodgkin’s lymphoma in May 2014, and this is the first presentation of the data that supported that designation. The results did not disappoint.

In the cohort of 23 heavily pre-treated R/R cHL patients (one-third of patients received six or more prior treatments), the overall response rate (ORR) was an exciting 87%, including four patients with complete response (CR, 17%), and 100% clinical benefit rate. The onsets of response were relatively fast, with first responses (both CR and PR) observed for within the first eight weeks of treatment (60% of responses occurred by week 8). The 24-week PFS was 86%, indicating durable responses from this immune blockade drug. Importantly, durable responses were observed in patients who had failed after prior stem cell transplant and/or prior treatment with Adcetris® (brentuximab vedotin, Seattle Genetics/Takeda). The overall safety profile was found to be similar to that observed in solid tumors: drug-related Grade 3 adverse events (AEs) included lymphopenia, gastrointestinal inflammation, increased lipase, pneumonitis, colitis and stomatitis and occurred in 22% of patients.

A large, multinational Phase II study (Registration; CheckMate 205, NCT02181738) was initiated in July 2014 and is ongoing in patients who relapsed after autologous stem cell transplantation (ASCT). If the clinical benefits observed in the Phase I study are confirmed in the CheckMate 205 trial, will PD-1 blockade introduce a paradigm shift in the treatment of cHL patients in the future in the same way that PD-1 blockade is doing now in solid tumors?

Story Two: Mixed results in other relapsed or refractory hematologic malignancies2

Results from the 69-patient cohort with non-Hodgkin’s lymphoma (NHL) malignancies (B-cell lymphoma, n=23; T-cell lymphoma, n=23; and multiple myeloma n=23) were reported separately. Most of the patients in this combined cohort were also heavily pre-treated (number of prior systemic treatments ranged from two to five, with over 20% of patients having received more than five prior treatments). The ORRs differed by patient subgroups. The ORR and CR rates in patients with B-NHL were 28% and 7%, respectively, with the highest objective ORRs observed in follicular lymphoma (40%) and peripheral T-cell lymphoma (40%). In the overall T-NHL population, the ORR was 17%. No responses were observed in multiple myeloma or in primary mediastinal B-cell lymphoma.

Again, the overall safety profile was similar to other Opdivo trials. Fatigue (13%) and pneumonitis (11%) were the most frequently observed drug-related AEs (all grades); the majority of pneumonitis was Grade 1 or 2, although there was one fatal event. Overall, 18% of drug-related AEs were Grade 3 and 2% were Grade 4  in this cohort.

This second part of the trial in hematologic malignancies demonstrated that Opdivo is safe and tolerable across many hematologic tumor types but that clinical benefit differs across the range of hematologic malignancies. The different responses from different hematologic malignancies may indicate that the PD-1 pathway may not function the same across all tumor types (genetic alteration of 9p24.1 was uncommon in the NHL population studied in this trial), or that tumor-specific mechanisms may affect the checkpoint blockade effect from PD-1 targeted drugs. The preliminary clinical data from this Phase I study are encouraging, but more studies are warranted before we can conclude that PD-1-targeted drugs will offer the same homerun/panacea effect in hematologic malignancies as many expect will be the case in solid tumors.

Encouraging results from Keytruda in Hodgkin’s lymphoma (KEYNOTE-013 Study)4

Merck presented the first results from a cohort of 31 R/R cHL patients enrolled in the KEYNOTE-013 study (the broader study population also included patients with myelodysplastic syndrome (MDS), mediastinal large B-cell lymphoma, multiple myeloma and NHL). The primary endpoint is CR rate, and secondary endpoints are ORR, PFS, overall survival and duration of response. Safety profiles of AEs with clinical interest to Keytruda were also part of the study objectives.

Keytruda achieved an excellent ORR of 66%, including CR rate of 21%, in this cohort of 29 R/R cHL patients, 100% of whom had failed after prior Adcetris and 69% of whom (n=20) had failed after a prior transplant. Most patients were heavily pre-treated (more than half of patients received five prior treatments). The overall clinical benefit rate was 86%, with only four patients having progressive disease. The clinical benefit rate in the 20 patients who were transplant failures was 90%, higher than that observed in the nine patients who were transplant-ineligible or refused transplant (78%). The overall safety profile was found to be similar to that observed in solid tumors, with Grade 3/4 treatment-related AEs occurring rarely.

These studies demonstrate that in cHL Opdivo and Keytruda are both active agents with similarly encouraging efficacy when measured by ORR (87% vs. 66%) or CR rate (17% vs. 21%). During a special session on immune checkpoint blockade, many questions were raised as to why there were such differences in response in different hematologic malignancies. The answers were mostly a straight and simple, “I don’t know.” Dr. Ansell from the Mayo Clinic provided excellent speculations on the biological reasons, namely, increased regulatory T-cells in lymphoma, presence of “exhausted” T-cells, increased immunosuppression ligands, and presence of intratumoral monocytes and follicular dendritic cells. Furthermore, the high responses to PD-1 drugs in cHL may be attributable to the genetic amplification at 9p24.1 and related PD-L1 overexpression that is common in cHL versus other hematologic malignancies. With these unique characteristics in mind, incorporating these promising immunologic agents into the current standards of care for lymphoma will present daunting clinical challenges for hematologists, immunotherapists and oncologists in the hematologic world.

Opdivo may be a step ahead with its Breakthrough Therapy Status in Hodgkin’s lymphoma and the ongoing CheckMate 205 study initiated in July 2014. Who the winner will be on the battlefield of hematologic malignancies remains to be seen, but if durable responses translate into prolonged PFS and overall survival then the ultimate winner is the patient.

References: 

  1. Armand et al., Abstract 289, ASH 2014
  2. Lesokhin et al., Abstract 291, ASH 2014
  3. Ansell et al., New Engl J Med, 2014 (DOI: 10.1056/NEJMoa1411087)
  4. Moskowitz et al., Abstract 290, ASH 2014

By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Linda Zhao, Ph.D., Director, Clinical and Scientific Assessment, Kantar Health

December 09, 2014 - 09:12 am Posted in ASH Conference Coverage comments0 Comments

Hodgkin’s lymphoma (HL) represents one of the more successful stories in oncology. The four-regimen combination of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) is the standard of care for newly diagnosed patients, and prognosis is excellent for patients who respond, demonstrating a five-year overall survival of approximately 80%.1 However, about 20% of patients relapse or are refractory to first-line therapy,2 and prognosis has traditionally been poor for this population, who typically receive salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT), which provides a cure rate of about 50%.3 For patients who relapse after auto-SCT, allogeneic SCT or best supportive care was the only an option. The approval of Adcetris® (brentuximab vendotin, Seattle Genetics/Takeda) in 2011 after second-line relapse or transplant failure changed this grim landscape and provided an important and effective new treatment option for patients. The compelling results from its pivotal Phase II trial, which showed an objective response rate (ORR) of 75% and median progression-free survival (PFS) of 5.6 months,4 helped pave the way to make Adcetris the new standard of care in relapsed/refractory patients. Indeed, about one-third of patients receive Adcetris following SCT failure or as second-line systemic therapy. 5 Given the effectiveness of Adcetris following SCT failure, one salient question arises: Can Adcetris also be used to minimize the risk of relapse post-SCT if given early as part of consolidation therapy following auto-SCT?

The AETHERA trial (SG035-0005; NCT01100502) was initiated to answer that very question, and interim efficacy data were presented at the American Society of Hematology (ASH) Conference held in San Francisco on Dec, 8, 2014.6  This trial enrolled 329 patients who had failed first-line therapy for newly diagnosed HL, treated them with salvage chemotherapy followed by auto-SCT, and then randomized them to consolidation therapy with Adcetris (1.8 mg/kg every three weeks for up to 12 months) plus best supportive care (BSC) versus placebo plus BSC. Patients were stratified into three high-risk groups at the time of enrollment/salvage chemotherapy: those with refractory HL, those who relapsed or progressed within one year from receiving front-line chemotherapy, and those who relapsed at or more than one year after front-line chemotherapy and had extranodal disease. Following completion of salvage chemotherapy, patients were restaged and stratified again based on response to salvage therapy prior to auto-SCT: complete response (CR), partial response (PR), or stable disease (SD); patients who had progressive disease following salvage therapy were excluded from the study.

As determined by independent review, the trial met its primary endpoint, and the results are compelling. The PFS was 43 months in the Adcetris arm and 24 months in the placebo arm (HR 0.57; 95%CI: 0.40-0.81, p=0.001). There was also some suggestion of a durable response by the PFS rate at two years, which was 63% in the Adcetris arm and 51% in the placebo arm. Subgroup analysis showed that the PFS benefit favored Adcetris in all pre-specified patient stratification groups. The OS was not significantly different between the two arms (p=0.62); however, patients who progressed on study were unblinded and allowed to cross over to the Adcetris arm, thus confounding the OS results. Indeed, 85% of patients in the placebo arm went on to receive Adcetris as subsequent therapy. As was seen with the pivotal trial that led to its approval, peripheral neuropathy of any grade was a common adverse event in these patients (any grade: 67% vs. 19% with placebo), as were neutropenia (any grade: 35% vs. 12%; Grade 3: 13% vs. 1%), nausea (any grade: 22% vs. 8%) and fatigue (any grade: 24% vs. 18%).

As with most therapeutics studied in a maintenance setting for patients in remission, an inevitable question is, “Does early maintenance therapy have a meaningful impact on the disease compared to treating the patient upon relapse?” The gold standard used across oncology to answer this question has been overall survival. The lack of survival benefit in AETHERA is concerning since it suggests that patients will do equally well (in the long run) whether they receive Adcetris in remission as maintenance or upon relapse. However, countering this stance is the argument that there is inherent value in delaying progression. In other tumors where this debate has occurred (e.g., non-small cell lung cancer, ovarian cancer), the PFS benefit has been in the range of two to four months. The 19-month improvement in median PFS seen in AETHERA is certainly more robust and supports enthusiasm among the hematologic oncology community. This level of PFS benefit is all the more exciting when we consider that many patients reached a point where they were enjoying a treatment-free remission since consolidation Adcetris was given for up to one year; at this interim analysis, one-half of patients who had discontinued therapy did so because they completed the 12 months of treatment in the absence of disease progression. Seattle Genetics has guided that it will seek approval for Adcetris in the maintenance/consolidation setting in early 2015, and the large level of benefit observed in this study is expected to support an expanded regulatory label.

The encouraging results in the relapsed and now in post-SCT maintenance settings support continued development of Adcetris in earlier lines of therapy for HL. The Phase III ECHELON-1 trial (NCT01712490) is examining whether Adcetris in combination with AVD will yield better efficacy than ABVD alone. For now, it looks as if Adcetris’ “hold” in relapsed/refractory HL is assured. One emerging area of need in HL is in patients who have relapsed or are refractory to Adcetris. While there is evidence that re-treatment with Adcetris following progression is efficacious,7 the potential for cumulative neuropathy may not make this a feasible option. In that vein, the PD-1 inhibitors have made their entry into the hematological malignancies. Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, BMS)8,9 were shown at ASH to be effective in the relapsed setting for HL following Adcetris. The data were from Phase I trials, so any firm conclusions will need to be reserved until later-stage studies are conducted, but these preliminary results are interesting. Additionally, Opdivo was tested in patients post-transplantation, which would put it in direct competition with Adcetris and may set the stage for an “immunotherapeutics showdown” between Opdivo and Adcetris. The high response rates and tolerable safety profile of PD-1 inhibitors may prove to be substantial competition for Adcetris down the road if Opdivo or Keytruda ultimately enter the relapsed/refractory HL market. For the time being, however, Adcetris will continue to be the dominant choice on the market for patients with relapsed HL.

References: 

  1. Kantar Health, CancerMPact® Patient Metrics, accessed December 8, 2014
  2. Derenzi et al., Genome Med, 2011
  3. Majhail et al., Bio Blood Marrow Transplant, 2006
  4. Younes et al., J Clin Oncol, 2012
  5. Kantar Health, CancerMPact® Treatment Architecture, accessed December 8, 2014
  6. Moskowitz et al., ASH 2014 (Abstract 673)
  7. Barlett et al., J Hematol Oncol, 2014
  8. Arman et al., ASH 2014 (Abstract 289)
  9. Moskowitz et al., ASH 2014 (Abstract 290)

By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Len Kusdra, Analyst, Clinical and Scientific Assessment, Kantar Health

December 08, 2014 - 11:12 am Posted in ASH Conference Coverage comments0 Comments

Proteasome inhibitors and immunomodulators (IMiDs) are the mainstay of therapy for multiple myeloma. For years, treatment has relied on Velcade® (bortezomib, Millennium/Takeda/Johnson & Johnson) and Revlimid® (lenalidomide, Celgene) as part of first-line and second-line therapy, usually in sequence. Recently, two advances have changed this paradigm. The first is the development of triplet therapy that combines both an IMiD and a proteasome inhibitor together with steroid: The RVD regimen (Revlimid, Velcade, dexamethasone) is now the most commonly used first-line regimen in the U.S. in transplant-eligible myeloma (37% of patients), and the similar VTD regimen (Velcade, thalidomide, dexamethasone) is most commonly used in these patients in Western Europe (25% of patients).1 The second recent advance is the introduction of next-generation agents within both of these classes – the proteasome inhibitor Kyprolis® (carfilzomib, Onyx/Amgen) was approved in the U.S. in July 2012 and the IMiD Pomalyst® (Imnovid® in Europe, pomalidomide, Celgene) was approved in the U.S. in February 2013 and in Europe in August 2013. Both Kyprolis and Pomalyst are currently approved for use in relapsed/refractory myeloma patients who have previously been treated with a proteasome inhibitor and an IMiD, but expectations are high that both drugs may ultimately be used in earlier lines of therapy.

Kyprolis received an accelerated approval in the U.S. based on a single-arm study. Confirmation of activity and European regulatory submission would be based on two randomized Phase III trials – the FOCUS trial (which compared Kyprolis versus best supportive care in third-line or later myeloma) and the ASPIRE trial. As was reported at the 2014 European Society of Medical Oncology (ESMO) annual meeting, the FOCUS trial failed to show significantly prolonged overall survival or progression-free survival (PFS) for Kyprolis versus best supportive care and also highlighted acute renal failure as a significant toxicity in this patient population.2 The failure of the FOCUS study placed greater onus on the ASPIRE trial to confirm activity of Kyprolis. The first results of the ASPIRE trial were reported at the 2014 American Society of Hematology (ASH) conference.3

ASPIRE randomized 792 patients to treatment with KRd (Kyprolis + Revlimid + low-dose dexamethasone) or Rd in myeloma patients who had received one to three prior regimens (median two prior lines). Unlike FOCUS, the ASPIRE trial did meet the primary endpoint, showing significantly prolonged PFS in favor of the KRd arm versus the Rd arm: 26.3 months versus 17.6 months, HR 0.69, p<0.0001. The triplet combination also significantly improved response rate (ORR 87.1% versus 66.7%; CR/VGPR 69.9% versus 40.4%; and CR/sCR 31.8% versus 9.3%), and there was a trend toward improved overall survival (two-year OS 73.3% versus 65.0%; medians not reached; HR 0.79, p=0.018, which did not cross the pre-specified stopping boundary for significance at this interim analysis). Although not reported in the presentation, Dr. Stewart noted during discussions that there was a low rate of post-study Kyprolis in both arms due to the lack of regulatory approval for Kyprolis in Europe. This lack of extensive crossover may prevent the OS analysis from being confounded and give us greater confidence when interpreting the data when final analysis is available.

Encouragingly, there were no safety signals, including no significant increase in renal failure (all grades: 8.4% versus 7.2%) or cardiac failure (all grades: 6.4% versus 4.1%). One potential reason for discordance between the FOCUS and ASPIRE trials in terms of renal toxicity may be the trial enrollment criteria: The ASPIRE trial predominantly enrolled patients with creatinine clearance (CrCl) of at least 50 mL/min, whereas the FOCUS trial included some patients with CrCl of less than 30 mL/min. Other adverse events were similar or only mildly increased in the KRd arm, with those increases typically being in the incidence of Grade 1/2 toxicity, which likely contributed to the significant improvement in EORTC Global Health Status that was observed in the KRd arm versus the Rd arm (p<0.0001).

Of note, in this study Kyprolis was administered for only the first 18 cycles, while the Rd regimen continued to be administered to patients until disease progression or intolerance (in both arms). The reasons for this are unclear although likely represent uncertainty with regard to long-term toxicity of the triplet regimen. Interestingly, the PFS curves reached maximal separation at the 18-month timepoint, after which they appeared to begin to converge. One wonders if an even greater level of PFS or OS benefit could have been achieved if Kyprolis had been maintained along with Rd until progression, especially in light of the safety data that suggest little concerning adverse events and the improved quality of life that was achieved during the 18-month period of triplet therapy.

What will be the impact of these results? Most significantly, the ASPIRE trial should support regulatory approval of Kyprolis in Europe. With the FOCUS trial having failed, ASPIRE is the nearest term hope to launch the drug in that market. In both the U.S. and Europe, the trial design should be sufficient for approval, since Revlimid plus dexamethasone is approved in the second-line setting. Is there a role for triplet therapy in second-line, especially in the new era of triplet therapy in first-line? Perhaps. Currently, U.S. physicians use second-line Kyprolis monotherapy most commonly in patients who received first-line RVD (24%), and only 7% use Rd post-RVD. While there is strong proof that Kyprolis is active in patients who were previously treated with Velcade, the use of Revlimid in two lines back-to-back may be less desirable to U.S. physicians, especially in an era when alternative IMiDs are available. This may limit adoption of KRd in second-line in the U.S. In contrast, European physicians use second-line Rd most commonly in patients who received first-line VTD, so the addition of Kyprolis to this standard regimen sequence might be easily adopted into practice. A key influence in both markets, however, will also be cost of therapy. Revlimid plus low-dose dexamethasone costs approximately $8,000 per month, and adding Kyprolis to that would bring the monthly cost to approximately $14,000. Patients will have to weigh the financial toxicity of this regimen against the efficacy gains, and while the U.S. tends to be more accepting of high-priced regimens, there could be a larger battle brewing in Europe. Last, but certainly not least, is the significant number of new agents with novel mechanisms of action (MOAs) that are currently in development in myeloma. When launched, will these novel MOAs be viewed more favorably than another proteasome-IMiD combination? On the horizon are HDAC inhibitors (the fate of panobinostat (Novartis) currently lies in the hands of the U.S. FDA and European Medicines Agency), anti-CD38 monoclonal antibodies (daratumumab (Genmab/Johnson & Johnson) and SAR650984 (sanofi) both presented encouraging data at ASH 2014; daratumumab has Breakthrough Therapy Status from the U.S. FDA and is already being studied in Phase III), and anti-SLAMF7 monoclonal antibodies (previously known as anti-CS-1; elotuzumab (AbbVie/BMS/Ono) also has Breakthrough Therapy Status and is currently in two Phase III trials), all of which are being studied in combination with a doublet regimen (either VelDex or Rd) in relapsed/refractory multiple myeloma.

However these various treatment options ultimately compete in the marketplace, patients will certainly be better off. With the KRd regimen demonstrating median PFS in excess of two years in a median third-line setting and overall survival estimated to be in excess of three years, these outcomes are certainly something for us to aspire to.

References:

  1. Kantar Health, CancerMPact® Treatment Architecture, accessed December 8, 2014.
  2. Ludwig H, et al., Abstract LBA28, ESMO 2014.
  3. Stewart AK, et al., Abstract 79, ASH 2014.

By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health

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