Jared Kaltwasser

A new study has confirmed the efficacy and safety of polatuzumab vedotin (Polivy) for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in real-world settings.

The study affirms earlier evidence that was obtained in more tightly controlled clinical trial settings. The research was 

Patients with R/R DLBCL who fail to respond or who relapse after 2 or more treatment regimens face very poor outcomes, wrote corresponding author Yafit Segman, MD, of Tel Aviv University in Israel, and colleagues. Existing regimens of therapy have resulted in overall survival (OS) rates of 4 to 6 months, leaving a significant gap of unmet clinical need.

However, the antibody-drug conjugate polatuzumab vedotin (pola) has shown promising signs that it could help fill that gap. In a phase 1 study of pola in patients with B-cell malignancies, single-agent pola showed objective responses in more than half (14 of 25) of heavily pre-treated patients with DLBCL.

 A combination with bendamustine-rituximab (Treanda-Rituxan; pola-BR), has been approved by the FDA to treat patients with R/R DLBCL who have had 2 or more prior ailed therapies and are not candidates for transplantation. A study published earlier this year3 showed that the pola-BR combination had superior progression-free survival (PFS) and OS rates when compared head-to-head with bendamustine-rituximab alone in patients with R/R DLBCL.

Still, Segman et al wanted to find out whether those positive data held up in real-world settings. To do so, they pulled data from 14 Israeli medical centers in which 47 heavily pre-treated patients with R/R DLBCL were given pola as part of a compassionate use program. Treatment was administered between June 2018 and November 2019, and all patients were at least 18 years old with 2 or more prior lines of therapy and at least 1 cycle of pola-based therapy. Among the 47 patients, 28 were treated with pola-BR and 4 were treated with pola in combination with bendamustine without rituximab (pola-B). The remaining 15 patients were treated with pola and rituximab but not bendamustine (pola-R).

In the overall study population, the median age was 66.1 years (interquartile range [IQR], 60.4-78.8). In patients treated with pola-B ± R, the median age was 66.3 years (IQR, 36.9-76.7), and among those treated with pola-R, the median age was 65 years (IQR, 56.7-83.5) Patients were excluded if they had central nervous system involvement or Richter transformation.

The median dose of bendamustine per cycle was 85 mg/m2 in patients receiving pola-B with or without rituximab. Patients receiving pola-B ± R got a median of 4 treatment cycles; those receiving pola-R had a median of 5 treatment cycles.

Twenty-five patients received granulocyte colony-stimulating factor (G-CSF) to prevent neutropenia, and 16 patients had early treatment discontinuation, mostly (12 cases) due to disease progression.

The overall response rate (ORR) was 61% in the overall population, with 40% achieving complete responses (CRs) and 21% achieving partial responses. In the 2 groups of patients who received pola-B ± R, the ORR was 62.5% and 37.5%, respectively. The pola-R group achieved an ORR of 60% with CRs in 47% of patients.

OS was a median of 8.3 months (IQR, 5.4-14.8), and the median PFS was 5.6 months (IQR, 2.97-7.97). Patients with Eastern Cooperative Oncology Group (ECOG) performance status scores of 2 or higher had shorter OS on average. Primary refractory and transformed DLBCL were linked with shorter PFS compared to relapsed disease and de novo DLBCL, respectively. The most common adverse events were infections and cytopenias.

“Our data show that polatuzumab-based regimen is an effective and tolerable treatment in relapsed/refractory DLBCL,” Segman et al concluded.

The investigators noted that their ORR and complete response results were equal to or better than the results of previously reported trials, and also superior to responses for third-line R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), and gemcitabine-based therapies.

Though the study had the advantage of providing real-world data, Segman and colleagues also noted some limitations, including a small sample size and patient-specific variability in bendamustine doses, which the authors said prevented them from drawing conclusions about the relative benefits of inducing the drug. The fact that patients were heavily pre-treated, with a median of 3 prior lines of therapy, also made it infeasible to compare the results of the present study to earlier research in patients with just 1 or 2 lines of prior therapy.

It was concluded that the pola-based treatment appears to be a viable new therapeutic option for patients with R/R DLBCL, including patients with high-risk characteristics.

“The high response rates that were achieved even when administered without bendamustine suggests that pola-based therapy may also serve as a bridge to [autologous stem cell transplant] or to [chimeric antigen receptor] T-cell therapy,” they said.

1. Segman Y, Ribakovsky E, Avigdor A, et al. Outcome of relapsed/refractory diffuse large B-cell lymphoma patients treated with polatuzumab vedotin-based therapy: real-life experience. Published online September 27, 2020. 

2. Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. 

. 2015;16(6):704-715. doi:10.1016/S1470-2045(15)70128-2

3. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. 

. 2020;38(2):155-165. doi:10.1200/JCO.19.00172

Articles

Patients with relapsed or refractory diffuse large B-cell lymphoma who have not found success in 2 or more lines of therapy face stiff odds, but new data suggest polatuzumab vedotin–based therapies may help improve outcomes.

Real-World Data Support Use of Polatuzumab Vedotin for Heavily Pretreated Patients with R/R DLBCL

Even in the midst of a pandemic, successful frontline therapy is still possible for patients with lymphoid malignancies like diffuse large B-cell lymphoma (DLBCL), according to a new journal article.

The short report comes from La Paz University Hospital in Madrid, Spain. Writing in the 

de la Cruz-Benito et al explained how they dealt with 18 cases of patients with DLBCL and high-grade B-cell lymphoma (HGBL) as the coronavirus disease 2019 (COVID-19) pandemic spread through the region between March 1 and May 31 of this year.

de la Cruz-Benito and colleagues said they found themselves navigating a number of difficult problems. Lymphoma itself can cause immune deregulation, but many therapies for the cancer cause significant immunosuppression. Thus, continuing with therapy could make a patient even more vulnerable to infection from the SARS-CoV-2 virus, but delaying treatment of lymphoma can also have significant detrimental effects. Additionally, the clinicians at La Paz University Hospital, like physicians everywhere, were operating without clear guidelines, given the novelty of the virus and the dramatic rapidity of its spread.

The study authors said they were most swayed by the potential negative impacts of delaying treatment, and so they set about to adapt their clinical practices in such a way as to continue planned therapy as safely as possible. In addition to screenings for COVID-19 symptoms, patients were not allowed to have visitors in the outpatient area, and follow-up was done via telemedicine whenever possible. Patients receiving immuno-chemotherapy were given SARS-CoV-2 tests before each treatment. Those with DLBCL were treated as outpatients with the R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy regimen. Patients with HGBL were treated with the dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride)regimen, with or without rituximab. Elderly patients were given attenuated regimens. Most patients received granulocyte colony stimulating factor (G-CSF) as a prophylactic to prevent neutropenia.

Of the cohort of 18 patients, 15 had DLBCL, the remaining 3 had plasmablastic lymphoma (n = 1) or HGBL not otherwise specified (n = 2).

Only one patient had neutropenic fever, which was observed on day 10 of the first cycle of chemotherapy, she was receiving G-CSF. The patient was given a test for COVID-19, which came back positive. She was then treated with hydroxychloroquine and azithromycin.

“Because of the viral diagnosis, thoracic CT was performed, showing bilateral ground‐glass opacities and 2 consolidations suggestive of viral disease,” the study authors wrote. “Antibiotic treatment with amoxicillin‐clavulanic acid was added, requiring an escalation strategy because of fever persistence, sequentially to levofloxacin (Levaquin), cefepime (Maxipime), and, finally, to meropenem (Merrem) and linezolid (Zyvox), reaching fever defervescence.”

The patient did not require oxygen therapy, and her secondary chemotherapy had to be delayed by 8 days until she had 2 consecutive negative COVID-19 tests.

Lymphopenia, which has been commonly reported among patients with COVID-19, was observed in 16 patients in the study. The patient with COVID-19 had a minimum of 0.05 × 109 lymphocytes/L. Half of the patients with lymphopenia had been treated with R-mini-CHOP.

de la Cruz-Benito and colleagues noted that current guidelines suggest avoidance of intensified regimens in order to decrease immunosuppression and related complications.

“In contrast, our centre decided to keep these regimens, giving priority to reaching the best disease control and outcome,” they wrote, adding that just one of their patients developed COVID-19 during treatment, and the patient had a mild case.

“Our study suggests that, despite maintaining aggressive treatments, it is possible to keep our patients free of COVID-19,” 

de la Cruz-Benito et al wrote. “However, further studies are needed to clarify the importance of prior or active chemotherapy in COVID-19 evolution.”

The authors said the issue of lymphopenia and SARS-CoV-2 also requires further investigation.

“It is noteworthy that minimum lymphocyte count was registered in our cohort in the only patient who was infected by SARS‐CoV‐2, simultaneous with the moment of COVID‐19 diagnosis,” they wrote.

Although they suggested that it is probable that the grade of lymphopenia correlates with severity of COVID-19, the only infected patient in their study had a favorable outcome.

More broadly, the authors noted that it was remarkable that only one patient in their cohort required inpatient treatment, suggesting that the use of the febrile neutropenia prophylactic G-CSF “may have influenced the low incidence of COVID-19 in our cohort.”

In their conclusion, the authors wrote that a number of factors, including hygiene, the prophylactic, and patient education could have contributed to their outcomes, but it’s important for health professionals to continue to update guidelines for the treatment of this patient group as more evidence becomes available.

de la Cruz-Benito B, Lázaro-Del Campo P, Ramírez-López A, et al. Managing the front-line treatment for diffuse large B-cell lymphoma and high-grade B-cell lymphoma during the COVID-19 outbreak. 

. Published online August 6, 2020. doi:10.1111/bjh.17066

Despite concerns about treatment-related immunosuppression, a report out of Spain suggests SARS-CoV-2 precautions can offset risk for patients with diffuse large B-cell lymphoma.

Patients With DLBCL Can Be Treated Successfully Amid Pandemic, Study Finds

Updated results from the phase 3 ALTERNATIVE study showed that dual HER2 blockade plus aromatase inhibition (AI) in post-menopausal women with HER2-positive, hormone receptor (HR)–positive metastatic breast cancer outperformed single HER2 blockade. 

,1 include numerical corrections that affected secondary analyses but did not affect the major conclusions of the study; nonetheless, the original ALTERNATIVE study, which was published in 2017, was retracted.

Typically, according to the investigators led by Stephen R. D. Johnston, PhD, of the Royal Marsden NHS Foundation Trust, in England, patients with HER2-positive cancers are given chemotherapy regardless of their HR status. Johnston and colleagues noted that targeted agents such as trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab-emtansine (T-DM1; Kadcyla) have significantly improved outcomes. However, the investigators said not all patients need or can tolerate chemotherapy. In such cases, anti-HER2 therapies paired with endocrine therapy can be a good option. Earlier research has suggested HER2-blockade with endocrine therapy (ET) in the first-line setting can improve outcomes over ET alone. In the ALTERNATIVE study, Johnston and colleagues set out to evaluate the use of a dual HER2-blockade, using a combination of trastuzumab and lapatinib.

“Dual targeting of HER2-positive tumors with [trastuzumab] and [lapatinib] is beneﬁcial because of differing mechanisms of action and because of the well-characterized synergistic interaction between them in HER2 [breast cancer] models,” the investigators wrote. “In the clinic, dual anti-HER2 blockade has been shown to improve outcomes in both the neoadjuvant and the metastatic setting compared with single HER2 blockade.”

The investigators enrolled a group of 355 patients with HER2-positive/HR-positive metastatic breast cancer who were not expected to undergo chemotherapy and who had previously received treatment with ET and had progressed on or after a trastuzumab and chemotherapy–based neoadjuvant/adjuvant regimen and/or in the first-line setting. The enrollees were randomly split into 3 groups: one group received lapatinib plus trastuzumab plus AI (n = 120), one group received trastuzumab plus AI (n = 117), and the final group received lapatinib plus AI (n = 118). Investigators chose whether patients received steroidal or nonsteroidal AI.

The primary end point was to evaluate progression-free survival (PFS) with lapatinib plus trastuzumab and AI versus trastuzumab plus AI.

The data showed that lapatinib plus trastuzumab and AI had a median PFS of 11 months (HR, 0.62; 95% CI, 0.45-0.88; 

 = .0063) versus 5.6 months on the trastuzumab-plus-AI. Overall response rate (ORR), clinical benefit rate, and overall survival were also superior in the lapatinib plus trastuzumab and AI group.

Comparing lapatinib plus AI to trastuzumab plus AI resulted in a median PFS of 8.3 months versus 5.6 months, respectively (HR, 0.85; 95% CI, 0.62-1.17; 

The rates of any-grade adverse events (AEs) were 92% with the triplet regimen, 74% with trastuzumab and AI, and 92% with lapatinib and AI. Most AEs were grade 1 or 2, and the most common were diarrhea, rash, nausea, and paronychia. Rates of serious AEs were similar across the 3 groups, though the group with lapatinib plus trastuzumab and AI had the lowest number of AEs leading to discontinuation.

Johnston and colleagues wrote that although it is too early to report survival data, early indications suggest the dual blockade is similarly superior.

The investigators noted that their results contrast with the lack of benefit shown in the adjuvant setting in the ALTTO2trial, and the minimal benefit shown in the APHINITY3 trial.

“This discrepancy may be the result, at least in part, of the excellent outcome with adjuvant single HER2 blockade with [trastuzumab], making the demonstration of additional benefit with dual blockade challenging,” they wrote. “Dual HER2 blockade may benefit only a small subject of high-risk patients.”

In conclusion, the authors said the results of this trial show a “clinically meaningful and robust” benefit with lapatinib plus trastuzumab and AI in patients previously treated with trastuzumab and ET, as well as a “relatively good” tolerability. Thus, they said, the data suggest patients with HER2-positive/HR-positive metastatic breast cancer who are not candidates for chemotherapy should be considered for this regimen.

“This combination can potentially offer an effective and well-tolerated chemotherapy-sparing alternative treatment regimen for patients for whom chemotherapy is not intended,” Johnston et al concluded.

Johnston SRD, Hegg R, Im SA, et al. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. 

. Published online August 21, 2020. doi:10.1200/JCO.20.01894

Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. 

 2016;34(10):1034-1042. doi:10.1200/JCO.2015.62.1797

von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. 

 2017;377:122-131. doi:10.1056/NEJMoa1703643

“Dual targeting of HER2-positive tumors with [trastuzumab] and [lapatinib] is beneﬁcial because of differing mechanisms of action and because of the well-characterized synergistic interaction between them in HER2 [breast cancer] models."

Updated ALTERNATIVE Results Favor Dual HER2 Blockade in HER2+/HR+ Metastatic Breast Cancer

Use of interim positron emission tomography (PET) scans to direct patient care has established a new standard treatment approach for patients with limited-stage diffuse large B-cell lymphoma (DLBCL). These findings, from the Intergroup, National Clinical Trials Network S1001 study, were reported 

DLBCL is the most common type of non-Hodgkin lymphoma in the United States. About 25% to 30% of patients with this malignancy will present with limited-stage disease. These patients have better overall survival (OS) rates than patients with advanced disease; however, they also face the constant risk of relapse.

Lead author Daniel O. Persky, MD, of the University of Arizona Cancer Center, and colleagues noted that their previous work conducted prior to the approval of rituximab (Rituxan) found that 3 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), followed by radiation therapy, led to better overall and progression-free survival rates in patients when compared to 8 courses of CHOP without radiation.

 Unfortunately, Persky and colleagues found that by year 9, the difference between the 2 regimens disappeared due to late relapses. Further research led to the stage-modified International Prognostic Index (sm-IPI), which enabled physicians to determine whether a particular patient had adverse risk factors. Those risk factors had a major impact on prognosis; the OS rate at 10 years in patients without risk factors was 89%.

More recently, though, rituximab has led to a major shift in the treatment of DLBCL. In high-risk patients, 3 cycles of R-CHOP followed by radiation therapy became the standard treatment, Persky and colleagues noted. Following up that therapy with radioimmunotherapy consolidation with ibritumomab tiuxetan (Zevalin) has been shown to decrease the rate of long-term relapse.

Persky et al noted that PET scans have been shown to be prognostic as an interim assessment, and some data have suggested that patients with negative PET scans have a low risk of relapse if they undergo a final round of R-CHOP and forgo radiation therapy.

In order to evaluate that premise, Persky and colleagues enrolled 158 patients, of whom 128 ultimately underwent central review of their interim PET/CT scans. All of the patients had nonbulky (<10 cm) stage I/II untreated DLBCL and received 3 cycles of R-CHOP therapy, after which the scans were taken.

If the scans were negative, patients were given one more cycle of R-CHOP. If a patient’s scan was positive, they were given field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Only 14 patients (11%) had positive interim PET scans following the initial 3 rounds of R-CHOP. After a median follow-up of 4.92 years, just 6 patients had relapses and 3 had died as a result of lymphoma, though an additional 11 died of causes unrelated to the cancer. The median age of those patients was 80 years. The median age in the overall trial was 62 years.

that the use of PET as an interim assessment would be a new strategy for many in the field. “Physicians treating lymphoma are using PET scans frequently for staging and response assessment, but their use in directing treatment at interim assessment is more controversial,” he said. “S1001 showed that interim PET could be used successfully to guide further therapy, and thus does represent somewhat of a shift.”

Persky et al found a 5-year progression-free survival (PFS) rate of 87%; 5-year OS rate was 89%. The authors reported that the OS and PFS rates were similar in both groups—those with negative scans who underwent another R-CHOP cycle and those with positive scans who subsequently had radiation therapy.

Persky and colleagues said their study is believed to be the largest prospective study of patients with limited-stage DLBCL in the United States since the introduction of rituximab.

“The trial establishes R-CHOP x 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients,” they concluded, as the study also showed good outcomes for older patients and those with bulky disease.

Persky and his colleagues conceded that their overall PFS rate was lower than their original goal of 93%. However, they said that shortcoming does not affect their overall conclusions, given the high risk of death among the age group.

“Considering these competing risks of death in an older population over a prolonged time period, we feel that the traditional end point of PFS does not adequately reflect the observed treatment effects, which was supported by our competing risk modeling,” they wrote.

The investigators also noted that not only did patients with positive interim PET scans end up with similar PFS and OS rates, but also no patient in that group had experienced a relapse as of the end of the study.

“We used a relatively high radiation dose (36 Gy plus a 9 Gy boost vs30-35 Gy in other studies) and a larger radiation field (IFRT [involved-field radiation therapy] vsinvolved-site RT) for these patients, which is no longer standard,” the study authors wrote. “In addition, ibritumomab tiuxetan is not approved in DLBCL. However, ibritumomab tiuxetan could have eliminated residual disease through the crossfire of radioisotope.”

The authors suggested that additional research would be needed to verify the outcomes among this group due to the small sample size in the current study.

1. Persky DO, Li H, Stephens DM, et al. Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. 

. Published online July 13, 2020. doi:10.1200/JCO.20.00999

2. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. 

. 1998;339(1):21-26. doi:10.1056/NEJM199807023390104

3. Shenkier TN, Voss N, Fairey R, et al. Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency. 

. 2002;20(1):197-204. doi:10.1200/JCO.2002.20.1.197

Use of interim positron emission tomography scans to direct patient care has established a new standard treatment approach for patients with limited-stage diffuse large B-cell lymphoma. These findings are from the Intergroup National Clinical Trials Network S1001 study.

Author | Jared Kaltwasser

Articles

Real-World Data Support Use of Polatuzumab Vedotin for Heavily Pretreated Patients with R/R DLBCL

Patients With DLBCL Can Be Treated Successfully Amid Pandemic, Study Finds

Updated ALTERNATIVE Results Favor Dual HER2 Blockade in HER2+/HR+ Metastatic Breast Cancer

PET-Guided Therapy Improves Outcomes in Patients With Limited-Stage DLBCL