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PER® Chemotherapy Foundation Symposium (CFS)

Ruth O’Regan, MD, professor, division head, Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, associate director, Clinical Research, University of Wisconsin Carbone Cancer Center, discusses the prognostic value of pathologic complete response (pCR) in HER2-positive breast cancer. 

Achieving a pCR to neoadjuvant therapy is associated with a favorable prognosis in this patient population as compared with those who have residual disease, says O’Regan. 

Notably, hormone receptor status appears to influence this prognostic value. For example, patients with HER2-positive, estrogen receptor&shy; (ER)—negative disease appear to derive a stronger benefit from achieving pCR as opposed to patients with HER2-positive, ER-positive disease, explains O’Regan. 

In general, the proportion of patients who achieve a pCR is lower in those with HER2-positive, ER-positive disease; therefore, it may be beneficial that pCR holds more prognostic value in HER2-positive, ER-negative cancer, O’Regan concludes. 

Ruth O’Regan, MD, discusses the prognostic value of pathologic complete response in HER2-positive breast cancer. 
 

Dr. O'Regan on Prognostic Value of pCR in HER2+ Breast Cancer

William K. Oh, MD, chief, Division of Hematology and Medical Oncology, professor of medicine and urology, Mount Sinai Hospital, discusses factors to consider when choosing a treatment for patients with metastatic hormone-sensitive prostate cancer (mHSPC). 

Abiraterone acetate (Zytiga) and apalutamide (Erleada) are approved for the treatment of men with mHSPC based on findings from the phase III LATITUDE and TITAN trials, respectively. Enzalutamide (Xtandi) is currently under review by the FDA for a supplemental new drug application in this indication based on data from the phase III ARCHES and ENZAMET trials. 

Choosing the optimal agent is difficult without cross-study comparisons, explains Oh. Moreover, docetaxel is another option in this setting. As such, patient comorbidities, age, and personal preference should be taken into consideration, says Oh. 

If patients opt for docetaxel, they can stop treatment after 6 cycles. Conversely, patients who receive AR-targeted therapy and androgen deprivation therapy, remain on treatment indefinitely, concludes Oh. 

William K. Oh, MD, discusses factors to consider when choosing a treatment for patients with metastatic hormone-sensitive prostate cancer. 
 

Dr. Oh on Choosing AR-Targeted Therapy Versus Chemotherapy in mHSPC

Adam M. Brufsky, MD, PhD, professor of medicine, associate chief, Division of Hematology/Oncology, co-director, Comprehensive Breast Cancer Center, associate director, Clinical Investigation, University of Pittsburgh Medical Center Hillman Cancer Center, discusses remaining challenges in breast cancer treatment.

Brufsky highlights the need to identify low-risk patients who do not need to receive treatment. 

For example, if a patient presents with a 3-cm low-grade tumor, a Nottingham score of 4, Ki-67 of 5%, 100% estrogen receptor expression, and 90% progesterone receptor expression, they can receive hormonal therapy alone, despite being premenopausal. Also, the patient does not require genomic testing, explains Brufsky. 

Similarly, in triple-negative breast cancer (TNBC), identification of predictive biomarkers to determine who could benefit without active therapy versus who requires additional treatments, such as immunotherapy, is an unmet need, says Brufsky. 

Though PD-L1 testing has been used frequently, deciding who to treat with immunotherapy without the use of additional biomarkers has proved to be a challenge in TNBC, concludes Brufsky.  

View more from the 2019 Chemotherapy Foundation Symposium

Adam M. Brufsky, MD, PhD, discusses remaining challenges in breast cancer. 
 

Dr. Brufsky on Challenges in Breast Cancer Treatment

Jason J. Luke, MD, FACP, associate professor of medicine, Division of Hematology/Oncology, director of the Cancer Immunotherapeutics Center Immunology and Immunotherapy Program, University of Pittsburgh Medical Center Hillman Cancer Center, discusses the treatment landscape of metastatic melanoma.

This space has seen rapid growth over the past 10 years, explains Luke. In the past, treatment was limited to chemotherapy and interleukin-2. 

A number of agents have been approved for the treatment of patients with metastatic disease, including combinations of BRAF and MEK inhibitors, as well as immunotherapy with PD-1 inhibitors alone or in combination with CTLA-4 inhibitors, explains Luke. 

These novel treatments have shown an overall survival benefit in the metastatic setting. Now, the field has 5-year overall survival data suggesting that at least 50% of patients who develop metastatic melanoma will live for at least 5 years, concludes Luke.  

Jason J. Luke, MD, FACP, discusses the treatment landscape of metastatic melanoma.

Dr. Luke on Treatment Options in Metastatic Melanoma

Three game-changing immunotherapy trials have transformed the treatment paradigm in frontline clear cell renal cell carcinoma (RCC). At the 

, Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, compared the findings from the three studies.

The 3 phase III randomized trials all had a control arm of single-agent sunitinib (Sutent): the CheckMate 214 trial

 (n = 1096) exploring nivolumab (Opdivo) plus ipilimumab (Yervoy); the KEYNOTE-426 trial

 (n = 861) assessing pembrolizumab (Keytruda) plus the tyrosine kinase inhibitor (TKI) axitinib (Inlyta); and JAVELIN Renal 101

 (n = 886), which explored avelumab (Bavencio) plus axitinib.

To compare the studies, Motzer highlighted several measures of comparison in the intent-to-treat populations across the 3 trials.

 Follow-up data are longest for nivolumab/ipilimumab at over 2 years (25.2 months). Follow-up is at about 1 year with pembrolizumab/axitinib (12.8 months) and avelumab/axitinib (12.0 months).

 The objective response rate (ORR) was slightly lower with nivolumab/ipilimumab (39%) compared with pembrolizumab/axitinib (59%) and avelumab/axitinib (51%). Motzer noted that the high ORR is a “salient feature” of TKI/immunotherapy combinations. However, complete response rate was higher with the dual immunotherapy regimen of nivolumab/ipilimumab (10.2%), compared with pembrolizumab/axitinib (5.8%) and avelumab/axitinib (3.4%).

The median PFS for nivolumab/ipilimumab versus sunitinib was 12.4 versus 12.3 months, respectively (HR, 0.98); 15.1 versus 11.1 months (HR, 0.69) with pembrolizumab/axitinib; and 13.8 versus 8.4 months (HR, 0.69) with avelumab/axitinib. Motzer said the longer median PFS with pembrolizumab/axitinib was “probably related to the TKI, since PFS seems to be most impacted by TKIs.”

Motzer explained that an OS benefit with nivolumab/ipilimumab (HR, 0.68) and pembrolizumab/axitinib (HR, 0.53) versus sunitinib has been demonstrated; however, the OS data are still not mature for avelumab/axitinib.

“For many oncologists, overall survival benefit trumps others, and so, for the most part, in choosing one treatment versus another in community practice, it’s been nivolumab/ipilimumab versus pembrolizumab/axitinib,” said Motzer.

Nivolumab/Ipilimumab Versus Pembrolizumab/Axitinib

Given the OS benefit demonstrated with nivolumab/ipilimumab versus pembrolizumab/axitinib, Motzer compared the CheckMate 214 and KEYNOTE-426 trials head to head.

A key component when comparing these trials, Motzer noted, is disease risk classification as determined by baseline characteristics. Risk evaluation categorizes patients’ status as either favorable, intermediate, or poor.

Among intermediate- and poor-risk patients, the data for the regimens in the 2 trials are similar. The ORR with nivolumab/ipilimumab was 42% versus 55.8% with pembrolizumab/axitinib. Complete response was higher with the nivolumab regimen at 9% versus 4.8%, respectively. Median PFS was 11.6 versus 12.6 months in the 2 arms, respectively. Motzer said both showed a “really good OS benefit,” with a 12-month OS rate of 80% (HR, 0.63) and 87% (HR, 0.52), respectively.

In favorable-risk patients in KEYNOTE-426, pembrolizumab/axitinib improved outcomes compared with sunitinib. In CheckMate 214, however, the ORR in the favorable-risk group was higher for single-agent sunitinib (52%) than nivolumab/ipilimumab (29%). The median PFS (25.1 vs 15.3 months) was also higher with sunitinib and the hazard ratio for OS was 1.45.

Motzer noted that with long-term follow-up, however, outcomes improve with nivolumab/ipilimumab in the favorable-risk group. Survival outcomes become similar between the 2 arms and the “durable complete response rate becomes higher with nivolumab/ipilimumab compared with sunitinib,” said Motzer.

Motzer also briefly touched on safety with the 2 trials, but did not note any differences that would heavily impact his treatment choice.

Based on the data he presented, Motzer said that for intermediate- and poor-risk patients, “Nivolumab/ipilimumab or pembrolizumab/axitinib are both good choices and the primary choices that I offer my patients. It’s often an individual decision for the risks/benefits of one versus the other with each patient.”

He added, “All things aside, I tip toward nivolumab/ipilimumab in these patients because of the fact that data are more mature and [positive] quality-of-life data are available.”

Regarding the favorable-risk population, Motzer cited the National Comprehensive Cancer Network (NCCN) Guidelines.

 “For patients who have favorable-risk disease, the preferred treatment according to NCCN is either pembrolizumab/axitinib or single-agent TKI; but, I also think nivolumab/ipilimumab is a possibility here if the patient and doctor feel the safety profile is acceptable.”

Motzer R. First-line metastatic renal cell carcinoma: what is the right choice? Presented at 

. November 6-8, 2019. New York, New York.

Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Kidney Cancer, version 2.2020. NCCN website. bit.ly/32pYknC. Published August 5, 2019. Accessed November 7, 2019.

Three game-changing immunotherapy trials have transformed the treatment paradigm in frontline clear cell renal cell carcinoma. At the 37th Annual CFS®, Robert J. Motzer, MD, compared the findings from the three studies.

Expert Compares Frontline Immunotherapy Studies in RCC

As PARP inhibitors (PARPi) have now moved into the frontline maintenance setting in ovarian cancer, researchers are now seeking to even further capitalize on use of these agents, including indications in treatment-naïve patients.

PARPi sensitivity is mostly due to germline or somatic BRCA mutations or other mutations leading to homologous recombination repair (HRD) deficiency, Leslie M. Randall, MD, explained at the 

 Randall, associate professor, director of medical education, and fellowship director in the Division of Gynecologic Oncology at the University of California, Irvine, said that platinum sensitivity may also serve as a marker for the successful use of PARPi.

“PARPi appears to be active across all settings, provided these tumors are high-grade serous endometrioid tumors,” Randall said.

Current indications for PARPi in ovarian cancer include second-line maintenance for patients with recurrent disease, third-line or later treatment for BRCA-mutated tumors, and HRD-positive tumor that are in the fourth-line or later setting following chemotherapy.

Randall said that by looking at the hazard ratios for progression-free survival (PFS) in trials leading to approvals for olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula), it is evident that these agents have significant efficacy in most patients, regardless of BRCA status. “If you look at patients with non

-mutated tumors, you see significant activity. Not to the degree of those with 

 mutations, but still significant,” she said.

When approved in the recurrent setting, the question concerning PARPi was whether or not these agents could be effective for frontline indications. The phase III SOLO-1 trial answered this question and served as the basis for which olaparib was approved in the frontline setting as maintenance following platinum-based chemotherapy in women with germline or somatic BRCA-mutated advanced ovarian cancer. Statistically significant improvements in median PFS were observed with olaparib compared with placebo (not reached vs 13.8 months; HR, 0.30; 95% CI, 0.23-0.41; 

According to data from a poster presentation at the 2019 American Society for Clinical Oncology Annual Meeting, olaparib use in SOLO-1 had similar efficacy across prognostic groups, including patients who had upfront surgery (HR, 0.31; 95% CI, 0.21-0.46), interval surgery (HR, 0.37; 95% CI, 0.24-0.58), residual disease following surgery (HR, 0.44; 95% CI, 0.25-0.77), or clinically complete (HR, 0.34; 95% CI, 0.24-0.47) or partial response (HR, 0.31; 95% CI, 0.18-0.52) following chemotherapy.

“Now, the frontline setting is the exciting playing field for PARP inhibitors. In the frontline setting, we are now where we were a couple of years ago in the platinum-sensitive recurrent maintenance space, showing efficacy for multiple [agents] in multiple settings,” Randall said.

Recently published data from the phase III PRIMA study showed improvement in median PFS with niraparib in the frontline treatment of patients with newly diagnosed disease who responded to platinum-based chemotherapy compared with placebo (13.8 vs 8.2 months; HR, 0.62; 95% CI, 0.50-0.76; 

 <.001), with even more significant responses observed in patients with HRD-positive disease (21.9 vs 10.4 months; HR, 0.43; 95% CI, 0.31-0.59; 

The PARPi veliparib has also produced promising responses in patients with high-grade serous ovarian cancer, when used in combination with carboplatin and paclitaxel followed by veliparib maintenance across all patient subgroups. The median PFS was 23.5 months with veliparib versus 17.3 months in patients treated with placebo (HR, 0.68; 95% CI, 0.56-0.83; 

 <.001). Similar to other PARPi therapies, the benefit was more significant in patients with BRCA mutations (HR, 0.44; 95% CI, 0.28-0.68; 

In the phase III PAOLA-1/ENGOT-ov25 trial, frontline maintenance was improved with the addition of olaparib to bevacizumab (Avastin), with a median PFS of 22.1 months compared with 16.6 months with placebo and bevacizumab in patients with newly diagnosed ovarian cancer following prior treatment with platinum-based chemotherapy (HR, 0.59; 95% CI, 0.49-0.72; 

PARPi is generally well tolerated, with adverse events (AEs) most commonly including hematologic events, nausea, vomiting, and fatigue.

“There is evidence to show that some patients do better with a lower starting dose, [such as those] who have a baseline platelet count of <150,000 [/µL] or a baseline weight of <70 kg,” Randall said. “Moft of these AEs happen within the first month and are often managed with dose delay or reduction. If you can get the patient to a steady state within the first month, these AEs generally stabilize and normalize over time.”

Based on evidence from early single-arm trials, there is a black box warning for myelodysplastic syndrome or acute myeloid leukemia for the 3 approved PARPi agents.

 The observed incidence of 1% to 2% has been consistently seen over time; however, there has been little difference between the experimental and control arms in placebo-controlled trials, suggesting that these events are not a PARPi class effect.

Randall concluded her presentation by looking to the future of PARPi use, which she says will focus on optimal treatment of HRD-negative patients and overcoming PARPi resistance—an issue almost akin to platinum-resistance&mdash;in PARPi combination trials.

Randall LM. PARP inhibitors for ovarian cancer: best thing since paclitaxel. Presented at: 

, hosted by Physicians’ Education Resource

, LLC. November 6-8, 2019; New York, New York.

Lynparza [package insert]. Washington, DE: AstraZeneca Pharmaceuticals LP; 2014. bit.ly/32qEVD8.

Zejula [package insert]. Waltham, MA: Tesaro. Inc; 2017. bit.ly/36GG391.

Rubraca [package insert]. Boulder, CO: Clovis Oncology, Inc. 2016. bit.ly/34BG9wP.

FDA approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based. FDA website. bit.ly/2NRYT4f. Published December 19, 2018. Accessed November 7, 2019.

Mathews CA, Moore KN, Colombo N, et al. Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): efficacy by surgical and tumor status in the phase III SOLO1 trial. 

. 2019;37(suppl 15;abstr 5541). doi: 10.1200/JCO.2019.37.15_suppl.5541.

Gonzalez-Martin A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer [published online September 28, 2019]. 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer [published online September 28, 2019]. 

Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. 

. 2019;30(suppl 5;abstr LBA2_PR). doi: 10.1093/annonc/mdz394.053.

As PARP inhibitors have now moved into the frontline maintenance setting in ovarian cancer, researchers are now seeking to even further capitalize on use of these agents, including indications in treatment-naïve patients.

Efforts Continue to Perfect PARPi Use in Ovarian Cancer

Quickly following on the approval of single agents, adjuvant immunotherapy combinations are quickly progressing through development, with promising signs of clinical activity seen in phase II studies, according to a presentation by Jeffrey S. Weber, MD, PhD, at the 

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was the first targeted therapy combination approved for advanced melanoma, and quickly found its way into the adjuvant setting. The pivotal study that led to approval of the combination, known as COMBI-AD, was designed prior to the approval of ipilimumab (Yervoy) in the adjuvant space, resulting in a placebo control arm. The trial enrolled those with 

“Targeted therapy has major activity in melanoma and is sometimes the treatment of choice for patients with rapidly progressing [tumors], high LDH [lactate dehydrogenase], and high disease burden,” said Weber, of the Laura and Isaac Perlmutter Cancer Center of NYU Langone Health. “Early on, it does seem like you do better with targeted therapy, whether that is maintained over time remains to be seen with longer follow-up with pembrolizumab and nivolumab.”

In long-term findings from the phase III COMBI-AD study,

 the 4-year relapse-free survival (RFS) rate was 54% with the combination compared with 38% in the placebo arm (HR, 0.49; 95% CI, 0.40-0.59). The distant metastases-free survival rate at 4 years was 67% in the dabrafenib/trametinib arm compared with 56% for placebo (HR, 0.53; 95% CI, 0.42-0.67). The OS rate at 3 years was 86% with the combination compared with 77% for placebo (HR, 0.57; 95% CI, 0.42-0.79; 

In addition to targeted combinations, immunotherapy combinations—such as nivolumab plus ipilimumab which was approved for the treatment of metastatic melanoma in 2015&mdash;are now being tested in the adjuvant setting. In early findings from the phase II IMMUNED study,

 adjuvant treatment with the combination for patients with high-risk stage IV disease demonstrated a 2-year RFS rate of 70% compared with 42% for nivolumab alone (HR, 0.40; 95% CI, 0.22-0.73) and 14% for placebo (HR, 0.23; 95% CI, 0.13-0.41).

“This looks phenomenal, and these are the patients with the worst outcomes. It’s fantastic, looks very good. It’s better than any of the other immunotherapy arms looking at 1-year and 2-year [data]. The 2-year data here look as good as the 1-year data for pembrolizumab or nivolumab alone if you were looking at stage III disease, but this is stage IV,” said Weber. “These data are very promising.”

One concern with the combination has been adverse events (AEs), which were higher with nivolumab and ipilimumab combined. In the study, treatment-related AEs of grade 3/4 in severity were experienced by 70.9% of patients in the combination group compared with 26.8% with nivolumab and 5.9% of patients in the placebo group.

The combination is being examined further in the phase III CheckMate 915 study, Weber said. This trial plans to randomize 1950 patients with stage III or IV disease to either nivolumab plus ipilimumab or nivolumab alone. The primary end point is RFS (NCT03068455). Results from the study are anticipated within the next few years, Weber said.

In addition to this adjuvant study, the combination of nivolumab and ipilimumab is being examined prior to surgery in the phase II OpACIN-neo study, Weber noted. This trial will look at a variety of doses for the combination with a primary end point focused on the occurrence of grade 3/4 immune-related AEs (NCT02977052).

Weber JS. Adjuvant Therapy for Melanoma. Presented at: 37th Annual CFS

, LLC; November 6-8, 2019; New York, New York.

Long GV, Hauschild A, Santinami M, et al. Updated relapse-free survival (RFS) and biomarker analysis in the COMBI-AD trial of adjuvant dabrafenib + trametinib (D + T) in patients (pts) with resected BRAF V600—mutant stage III melanoma. 

. 2018;29(suppl 8;abstr LBA43). doi: 10.1093/annonc/mdy424.053.

Schadendorf D, Hassel JC, Fluck M, et al. Adjuvant immunotherapy with nivolumab (NIVO) alone or in combination with ipilimumab (IPI) versus placebo in stage IV melanoma patients with no evidence of disease (NED): A randomized, double-blind phase 2 trial (IMMUNED). 

. 2019;30(suppl 5;abstr LBA67). doi: 10.1093/annonc/mdy394.064.

Quickly following on the approval of single agents, adjuvant immunotherapy combinations are quickly progressing through development, with promising signs of clinical activity seen in phase II studies, according to a presentation by Jeffrey S. Weber, MD, PhD, at the 37th Annual CFS®.

Adjuvant Immunotherapy Combinations on Horizon for Melanoma

Richard R. Furman, MD, professor of medicine, Morton Coleman, MD Distinguished Professor of Medicine, director, CLL Research Center, Weill Cornell Medicine, attending physician, NewYork-Presbyterian Hospital, discusses the role of prognostic markers in high-risk chronic lymphocytic leukemia (CLL). 

There are several important prognostic markers in CLL, explains Furman. For example, those that indicate resistance to BTK inhibition, such as cysteine 481, and those that indicate the likelihood of developing Richter’s transformation.

Richard R. Furman, MD, discusses the role of prognostic markers in high-risk chronic lymphocytic leukemia. 
 

Dr. Furman on Prognostic Markers in High-Risk CLL

Robert J. Motzer, MD, medical oncologist, head, Kidney Cancer Section, Genitourinary Oncology Service, Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, and 2016 Giant of Cancer Care

 in Genitourinary Cancer, discusses the first-line treatment landscape of metastatic clear cell renal cell carcinoma (RCC). 

Historically, first-line treatment for this patient population has consisted of TKI monotherapy with either sunitinib (Sutent) or pazopanib (Votrient), explains Motzer. 

Recently, 3 randomized phase III trials demonstrated improved outcomes with combined checkpoint inhibition versus sunitinib. Specifically, the KEYNOTE-426, JAVELIN Renal 101, and CheckMate-214 trial in which the combinations of axitinib (Inlyta)/pembrolizumab (Keytruda), axitinib/avelumab (Bavencio), and ipilimumab (Yervoy)/nivolumab (Opdivo) were evaluated, respectively. Data from these trials led to the regulatory approval of these combinations.

Among these regimens, axitinib/pembrolizumab and ipilimumab/nivolumab have become the frontline standards having demonstrated the most robust improvement in overall survival, says Motzer.

Robert J. Motzer, MD, discusses the first-line treatment landscape of metastatic clear cell renal cell carcinoma. 
 

Dr. Motzer on First-Line Treatment of Metastatic RCC

Novel combinations of biologic therapies, third-generation TKIs, and chemotherapy could lead to significantly higher cure rates for adult patients with acute lymphoblastic leukemia (ALL), with a number of early stage studies already showing promising results, according to Hagop M. Kantarjian, MD, at the 

“If we can find new antibodies that are effective not only as single agents, [but can be added] to chemotherapy, my hope, or prediction, is that in adult ALL we will improve the cure rates to be the same as [those seen in] childhood ALL, with much less chemotherapy,” said Kantarjian, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “I think the future might be the third-generation agent ponatinib, to which we add antibodies, rather than chemotherapy.”

Outcome are less favorable in adult patients with ALL compared with pediatric patients, mainly caused by difference cytogenetics. Approximately 50% of adult patients with ALL have Philadelphia chromosome-positive (Ph+) or Ph-like ALL, which denotes a poor prognosis, compared with 15% in pediatric patients.

Over the past few years, a number of promising therapies have gained single-agent approvals for the treatment of adult patients with refectory ALL, including chimeric antigen receptor (CAR) T cells, blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and ponatinib (Iclusig). Now, as more is learned, many of these agents are being combined in earlier settings, with not only promising response rates but also overall survival (OS) findings.

Findings from a phase II study exploring hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone with methotrexate and cytarabine) plus ponatinib were presented at the 2019 European Hematology Association (EHA) meeting.

 In this study, the combination led to a complete remission (CR) rate of 100% and a complete molecular remission (CMR) rate of 77% for patients with newly diagnosed Ph+ ALL. At 3 years, 79% of patients continued to have a CR and the 3-year OS rate was 77%, which is above the historical OS rate of approximately 50%, Kantarjian noted.

Findings from the study led researchers to question whether similar results could be achieved in the absence of chemotherapy. To this end, the phase II D-ALBA study was conducted, looking at the combination of dasatinib (Sprycel) plus blinatumomab as a frontline treatment for adult patients with Ph+ ALL. Preliminary findings from the study were presented at the 2019 EHA meeting.

In the preliminary findings, the molecular response rate was 54% with blinatumomab and dasatinib, which included a CMR rate of 29%. The 12-month OS rate was 96% and 92% of patients were free of disease and alive at 12 months. The ability of blinatumomab to improve molecular responses in this study further places importance on minimal residual disease (MRD) as an end point, Kantarjian said.

In March 2018, the FDA granted an accelerated approval to blinatumomab for adult and pediatric patients with B-cell precursor ALL following first or second complete remission (CR1 and CR2, respectively) with MRD greater than or equal to 0.1%. The approval was based on findings from the single-arm BLAST trial, in which blinatumomab induced MRD-negativity in 85% of patients in CR1 and for 72% of those in CR2.

“Blinatumomab now is an established treatment for patients who are MRD-positive in complete remission,” said Kantarjian. “One could use it before the allogeneic transplantation and then consider whether transplant is needed.”

In the absence of effective TKIs for Ph-negative (Ph-) ALL, other novel combinations are under exploration. Investigators at the MD Anderson launched a phase II study looking at mini-HCVD (dose-reduced and hyperfractionated cyclophosphamide, vincristine, and dexamethasone with methotrexate and cytarabine) plus inotuzumab ozogamicin with or without blinatumomab in patients with relapsed/refractory Ph- ALL.

 These therapies could have synergistic activity, as blinatumomab targets CD19 and inotuzumab targets CD22, Kantarjian noted.

Across all patients (n = 89), whether they received blinatumomab or not, the objective response rate (ORR) was 79%. The ORR in the first salvage setting was 91%. In the second and third salvage settings, the ORRs were 56% and 60%, respectively. Eighty-two percent of patients were MRD-negative. At a median follow-up of 31 months, the 2-year OS rate was 39% and the median OS was 14 months. The median duration of CR was 30 months. In those receiving inotuzumab ozogamicin alone in prior studies, the 2-year OS rate was 18% and the median OS was 6 months, Kantarjian said.

In the study, the dose of inotuzumab ozogamicin was separated into a weekly fractionated dose to avoid veno-occlusive disease (VOD). Across the full study, grade 3/4 VOD occurred in 6% of patients, which was less than in prior studies. “The veno-occlusive disease rate is down to about 6%, which is the baseline when you conduct allogeneic transplantation,” Kantarjian said.

 the combination of mini-HCVD plus inotuzumab ozogamicin with or without blinatumomab was also tried in older patients with ALL. In this study, the ORR was 98%, all of which were CRs or CRs with incomplete platelet or hematologic recovery. There were no early deaths in the study and the MRD response rate was 95%. The median OS was not yet reached, and the 3-year OS rate was 56%. Kantarjian estimated median OS at this time to be around 45 months.

Additional studies are being designed to further test the combinations, Kantarjian noted. A study is being designed for ponatinib plus blinatumomab in Ph+ ALL and another study is being designed for inotuzumab ozogamicin with blinatumomab with chemotherapy for Ph- ALL.

Kantarjian H. Immuno-Rx in the management of adult-elderly ALL in 2019. Presented at: 

, LLC; New York, New York, November 6-8, 2019.

Short N, Kantajian H, Ravandi F, et al. Updated results of a phase II study of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Presented at: 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract P518. bit.ly/2Nm1xQQ.

Chiaretti S, Bassan R, Vitale A, et al. A dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ all patients. preliminary results of the GIMEMA LAL2116 D-ALBA trial; on behalf of GIMEMA acute leukemia working party. Presented at: 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract S1617. bit.ly/2JVMT0E.

FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia [press release]. FDA. Published March 29, 2018. bit.ly/2NMRVha. Accessed November 6, 2019.

Sasaki K, Kantarjian HM, Ravandi F, et al. Sequential combination of low-intensity chemotherapy (mini-hyper-CVD) plus inotuzumab ozogamicin with or without blinatumomab in patients with relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL): a phase 2 trial. 

Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. 

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Novel combinations of biologic therapies, third-generation TKIs, and chemotherapy could lead to significantly higher cure rates for adult patients with acute lymphoblastic leukemia, with a number of early stage studies already showing promising results, according to Hagop M. Kantarjian, MD, at the 37th Annual CFS®.