The battlefield extends into hematologic malignancies – continuing the race between PD-1-targeted therapeutics

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.


  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

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