Darcy Lewis

The frequency of mutations in patients with mantle cell lymphoma (MCL) has a tendency to increase at clinical turning points like disease relapse and progression compared with at the time of diagnosis, according to a systemic review and meta-analysis published in 

A team of authors from the MD Anderson Cancer Center, Mayo Clinic, and Pennsylvania State College of Medicine conducted this analysis to examine the prevalence of genetic mutations in patients with MCL, determine methods of sequencing and genotyping, and demonstrate the possible clinical significance of these mutations.

The authors, led by Michael L. Wang, MD, of MD Anderson, reviewed the genetics of 2275 MCL tumor or bone marrow samples taken at baseline and observed that nearly half (43.5%) contained mutated 

. The next most frequently mutated gene was 

 (20.2%). Cytogenetic methods also detected aberrations in 

 (20.8%). Additional common baseline mutations included 

The study authors also identified the genes with the highest mutational frequency difference (>5%). These include 

TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A,

Based on the pooled analysis, the study authors focused on 32 genes, out of 164, that were found to be frequently mutated in at least one of the studies. Wang et al found the overall probability of having a genetic mutation in these 32 genes to be 11.3% at baseline (95% CI, 9.3%-13.4%). For patients tested again after relapse or progression, the probability of having a mutation in one of these genes had increased to 18.4% (95% CI, 14.9%-22.4%). “The oncogenic role of these aberrations as driver mutations in clonal evolution and expansion should be further studied,” they wrote. “Targeted panels for MCL could be constructed using genes with the highest mutational rate combined with recurrently mutated regions of the genes to understand their clinical relevance in the era of novel precision therapies.”

At disease progression, the most common genetic mutations were 

The biggest difference from baseline to disease progression was seen in the 

gene, where the frequency was 26.8% at baseline up to 43.0% at disease progression (Bayesian probability, 0.998).

The authors performed a literature search of 3 major databases for original studies that reported genetic mutations in patients with MCL, including randomized clinical trials, prospective studies, retrospective studies, and case reports. They excluded studies that reported only conventional cytogenetics such as gains, deletions, and translocations, as well as gene expression data without genetic mutation data. 

Extracted data included mutational data (whether a gene was mutated), type of study (observational or experimental), the technology used to analyze mutations, sample collection time point (baseline/diagnosis, relapse, progression), and if a specific treatment or therapy was named in the study. They collected both study-level and patient-level data. After initially identifying 1577 unique studies, Wang et al culled studies that didn’t meet the inclusion criteria until they were left with 32 to include in the final analysis.

The 32 included studies included 2275 samples from 2127 patients. Overall, 2045 of 2127 patients with MCL had baseline samples with genetic mutation information for at least 1 of the 32 genes. Studies from the pre-genomic era generally used techniques such as Sanger sequencing, probed fluorescence in situ hybridization, and polymerase chain reaction to identify mutations. More recent studies have frequently used single-nucleotide polymorphism arrays and next-generation sequencing (NGS).

Wang et al urged the inclusion of all genes with >5% increase in mutational frequency in future genomic and functional studies “to understand their role in the relapse and progression of MCL and be included in targeted NGS panels,” they wrote. “The patient-level data of prevalent mutations in MCL provide additional evidence to existing literature highlighting the importance of molecular variability in advancing precision medicine initiatives in MCL.”

In assessing their paper’s strength and weaknesses, Wang et al emphasized their inclusion of patient-level data as increasing the quality and reliability of their data. Despite their efforts, they note that their study is subject to the small-study effect due to the rarity of MCL and the relatively low number of genetic studies done to date. Additionally, MCL tissue banks are used for many genotyping/sequencing studies, so it’s possible that some patient samples have been used in multiple studies. “However, we believe that each patient observed in the 32 studies was genotyped/sequenced uniquely for that particular study and represents an independent observation,” they wrote.

The authors also noted that additional articles reporting mutations in patients with MCL were published after their study period: “These articles describe prevalent mutations similar to those reported in our analysis, including 

1. Hill HA, Qi X, Jain P, et al. Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis. 

 2020;4(13):2927-2938. doi:10.1182/bloodadvances.2019001350.

2. Jain P, Zhang S, Kanagal-Shamanna R, et al. Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL. 

 2020;4(6):1038-1050. doi:10.1182/bloodadvances.2019001396

3. Streich L, Sukhanova M, Lu X, et al. Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: a multi-institutional study. 

 2020;59(8):484-494. doi:10.1002/gcc.22849

4. Swenson S, Gilbreath T, Vahle HE, et al. UBR5 HECT domain mutations in mantle cell lymphoma control maturation of B cells 

. 2020;136(3):299-312. doi:10.1182/blood.2019002102

5. Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. 

 2020;95(6):623-629. doi:10.1002/ajh.25796

6. Pararajalingam P, Coyle KM, Arthur S, et al. Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing. 

. 2020;136(5):572-584. doi:10.1182/blood.2019002385

Articles

The frequency of mutations in patients with mantle cell lymphoma has a tendency to increase at clinical turning points like disease relapse and progression compared with at the time of diagnosis, according to a systemic review and meta-analysis.

Meta-Analysis Highlights Commonly Mutated Genes in Mantle Cell Lymphoma

For more than 30 years after cisplatin received its first approval from the FDA in 1978, platinum-based therapies remained the only treatment for ovarian cancer. That era ended in 2014 with the introduction of the VEGF inhibitor bevacizumab (Avastin) and the PARP inhibitor olaparib (Lynparza), both of which have amassed impressive numbers of FDA approvals in the ensuing years. This is an exciting time in the ovarian cancer space as the use of approved agents are being refined. With multiple treatment options available, clinicians will have to sort through myriad research findings to apply their best clinical judgment in treating each individual patient.

In May, FDA approval for maintenance treatment of ovarian cancer was granted to the combination of olaparib with bevacizumab based on findings from the PAOLA-1 trial (NCT02477644).

 In the phase 3 trial, investigators compared maintenance olaparib plus bevacizumab to bevacizumab alone in patients with newly diagnosed, advanced ovarian cancer following response to first-line platinum-based chemotherapy combined with bevacizumab, regardless of 

Patients were randomized 2:1 to receive 300-mg olaparib tablets (n = 537) or placebo (n = 269) for up to 24 months. All 806 patients received bevacizumab at 15 mg/kg every 3 weeks for up to 15 months total. The primary end point was the time from randomization until investigator-assessed disease progression or death. With a median follow-up of 22.9 months, there was a statistically significant improvement in median progression-free survival (PFS), at 22.1 months for the combined regimen and 16.6 months for the placebo group (HR, 0.59; 95% CI, 0.49-0.72; 

In patients with tumors positive for homologous recombination deficiency (HRD), including those with 

-mutant tumors, the hazard ratio for disease progression or death was 0.33 (95% CI, 0.25-0.45). In patients with HRD-positive tumors that did not have 

 mutations, the hazard ratio for disease progression or death was 0.43 (95% CI, 0.28-0.66). These findings led the investigators to conclude that the addition of maintenance olaparib provided a significant PFS benefit to patients with advanced ovarian cancer receiving first-line standard therapy that included bevacizumab, especially for patients with HRD-positive tumors (TABLE).

“Given that the estimated median PFS in the subgroup of patients with HRD-positive tumors was 37.2 months in the olaparib-with-bevacizumab arm and 17.7 months in the placebo-plus-bevacizumab arm, these are impressive results,” Bradley Monk, MD, US Oncology medical director of gynecologic oncology research and a professor at the University of Arizona College of Medicine–Phoenix, said in an interview with 

Potential synergy between PARP inhibitors and antiangiogenics has been the motivation behind exploring the use of olaparib with other novel agents. Results from one such pairing, olaparib with the investigational VEGFR inhibitor cediranib (AZD2171), were presented at the American Society of Clinical Oncology 2020 (ASCO 2020) Virtual Scientific Program.

Investigators designed the phase 3 NRG-GY004 trial (NCT02446600) to expand on earlier phase 2 findings that the combination of cediranib and olaparib improved PFS over olaparib alone for patients with platinum-sensitive, high-grade serous/endometrioid ovarian cancer, regardless of 

 mutation status. This is the first phase 3 trial to compare an all-oral nonplatinum regimen to platinum-based chemotherapy in patients with platinum-sensitive ovarian cancer.

Patients (n = 565) were randomized 1:1:1 to receive either a carboplatin-based doublet regimen, daily cediranib plus twice-daily olaparib, or olaparib 300 mg twice daily. After a median follow-up of 29.1 months, objective response rates (ORRs) were 71.3% for carboplatin doublet, 69.4% for cediranib/olaparib, and 52.4% for olaparib alone, and the combination did not meet the primary end point of PFS improvement. However, comparable clinical activity to standard chemotherapy in the overall population and substantial activity in patients with germline 

 mutations led the investigators to conclude that the nonplatinum regimen may still have utility in certain patient sets.

According to Shannon N. Westin, MD, MPH, associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, the FDA approval of PARP inhibitors during NRG-GY004’s active period has made assessing this trial difficult. “What’s unclear is how much [patients receiving newly approved PARP inhibitors in an NRG-GY004 protocol violation] might have impacted the progression-free survival and overall benefit,” she said. “This trial wasn’t designed to show noninferiority or equivalence, so you have to be cautious. [The results don’t] mean there was an obvious lack of benefit from the nonplatinum drugs; they just didn’t do better.”

Niraparib In another noteworthy development in the PARP inhibitor space, niraparib (Zejula) received FDA approval in April for use as a single agent in first-line maintenance in patients with advanced ovarian cancer. Findings from the phase 3 PRIMA trial (NCT02655016) served as the basis of this designation.

Patients with newly diagnosed advanced ovarian cancer who had responded to first-line platinum-based chemotherapy were randomized 2:1 to receive niraparib or placebo once daily. The primary end point was PFS, in both the overall population and patients who had HRD-positive tumors.

Slightly more than half of the 733 patients in the trial population had tumors with HRD. Within this HRDpositive subgroup, patients randomized to receive niraparib experienced a median PFS of 21.9 months compared with 10.4 months for the placebo group (HR, 0.43; 95% CI, 0.31-0.59; 

 < .001). In the overall trial population, patients in the niraparib group had a median PFS of 13.8 months versus 8.2 months for those in the placebo group (HR, 0.62; 95% CI, 0.50-0.76; 

 < .001). Positive results in both the overall cohort and the HRD-positive subgroup led the investigators to conclude that niraparib extended PFS among patients with advanced ovarian cancer regardless of HRD status.

Monk, who was senior author of the trial report, noted that the FDA single-agent frontline approval—when compared against the study’s start date—occurred at a pace he calls “unprecedented.”

Recent clinical trials examining immunotherapeutics have shown promise in the treatment of what was once considered an “immunologically cold” tumor type.

Final results from the KEYNOTE-100 trial (NCT02674061) were presented at ASCO 2020.6 An interim analysis of trial data had found that monotherapy with pembrolizumab (Keytruda) showed modest clinical activity in patients with recurrent advanced ovarian cancer after a median follow-up of 16.9 months; the ORR was 8.0% in all patients and did not show a clear correlation with the number of prior lines of therapy.

The trial included 376 patients divided into 2 cohorts: cohort A (n = 285) had received 2 or fewer prior chemotherapy lines for recurrent ovarian cancer and had been treatment free for 3 to 12 months. Patients in cohort B (n = 91) had received 3 to 5 prior lines of chemotherapy and had been treatment free for at least 3 months. Patients received pembrolizumab 200 mg every 3 weeks for 2 years, with ORR as the primary end point.

At the final analysis, the median follow-up had increased to 37.8 months. The ORR for both cohorts combined was 8.5%. In cohort A, the ORR was 8.1% versus 9.9% in cohort B. Additionally, patient outcomes were analyzed by tumor PD-L1 expression level. “There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts,” Ursula A. Matulonis, MD, who is chief of the Division of Gynecologic Oncology at the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts, said during her presentation of the data. “Median OS [overall survival] was 18.7 months, with a trend toward a longer OS with increasing PD-L1 expression in both cohorts.”

Westin noted that the ORR was comparable to that seen with chemotherapy. “Pembrolizumab is not the home run [in ovarian cancer] that we see in bladder or lung cancer, but KEYNOTE-100 shows that, if your patient benefits from immunotherapy, it’s a durable benefit. This study also shows a strong benefit in clear cell ovarian cancer, which tends to be very chemoresistant, so this response was impressive.”

One of Westin’s own immunotherapy studies has garnered attention following presentation of its results at the 2020 American Association for Cancer Research Virtual Annual Meeting I. The phase 2 trial examined the safety of durvalumab (Imfinzi) combined with chemotherapy in patients with newly diagnosed advanced ovarian cancer (NCT02726997).

The study enrolled 18 patients with untreated, stage III or IV ovarian cancer. The study regimen consisted of a baseline tissue biopsy, followed by durvalumab at 750 mg every 2 weeks, weekly paclitaxel at 80 mg/m

, and AUC 6 dosing of carboplatin every 3 weeks.

After a median follow-up of 13 months, median OS was not reached. At 18 months, the OS rate was 69%. The median PFS was 14.5 months, and almost half the patients experienced disease progression.

Westin and colleagues obtained 55 tumor specimens from 9 patients before and after treatment. Among 211 proteins identified, 13 were determined to show differential expression between pre- and posttreatment tissues. A press release from MD Anderson Cancer Center noted that the authors had discovered 1 downregulated protein, XBP1, and 12 upregulated proteins, including PAR, ARID1A, and STING.

“We’re hoping this translational work can help us guide combination therapy because so far trials have shown that the addition of a checkpoint inhibitor to chemotherapy didn’t improve progression-free survival,” Westin says. “What we’re trying to do is move toward more personalized precision medicine based on what actually happens inside the tumor.”

Another eagerly watched immunotherapy trial that was presented at ASCO 2020 involves the use of Vigil in combination with atezolizumab (Tecentriq) in patients with recurrent ovarian cancer (NCT03073525).10 According to Monk, who was an author on the trial report, Vigil is a personalized precision vaccine “constructed from autologous tumor tissue transfected with a DNA plasmid encoding GM-CSF and bi-shRNA- furin, thereby creating TGFβ expression control and enhancing immune activation.”

The trial is a randomized, 3-part, phase 1 safety study of the Vigil vaccine in combination with atezolizumab in patients with recurrent ovarian cancer. Part 2 of the trial is a randomized crossover study in which patients start with 2 cycles of either the vaccine (1 × 10

cells/ mL) or atezolizumab (1200 mg) before taking the combined regimen.

According to preliminary results for 21 patients in part 2, median OS was not reached in the Vigil-first group versus 10.8 months in the atezolizumab-first group. A subset analysis of patients with wild-type 

 demonstrated a more signifi cant OS benefi t for the 7 Vigil-first patients, with median OS not reached versus 5.2 months (HR, 0.12; 1-sided 

 = .015) for the 7 atezolizumab-first patients. Initial toxicity reports favored the Vigil-first cohort, with only 3% of patients developing grade 3/4 toxicities compared with 17% of the atezolizumab-first group. The investigators concluded that the combination of Vigil plus atezolizumab is safe, with trial data suggesting lower toxicity and a significant OS advantage in patients with recurrent 

 wild-type ovarian cancer treated with Vigil first, followed by the combined regimen.

Gene therapy with the investigational agent VB-111 (ofranergene obadenovec) has also garnered widespread interest among clinicians and investigators alike. VB-111 is a targeted anticancer gene therapy designed for a variety of solid tumors. It has a dual mechanism: a broad antiangiogenic effect and the induction of a tumor-directed viral immune response. Investigators presented interim findings from the OVAL trial (NCT03398655) at ASCO 2020.

The phase 3 study randomized patients with heavily pretreated recurrent platinum-resistant epithelial ovarian cancer 1:1 to receive VB-111 (1 × 10

 viral particles) or placebo, both with weekly paclitaxel at 80 mg/m

). Patients were stratified by the number of prior treatment lines, prior antiangiogenic therapy, and platinum-refractory disease status.

"What we’re trying to do is move toward more personalized precision medicine based on what actually happens inside the tumor." – Shannon N. Westin, MD, MPH

OVAL’s primary end points were OS, safety, and tolerability. The planned total enrollment was 400 patients; currently, 80 patients have been enrolled in the United States and Israel, with enrollment expansion to Europe planned for 2020. In late March, an independent panel determined that the VB-111 arm met the interim prespecified benchmark of a CA-125 ORR at least 10% higher compared with paclitaxel-alone. In the first 60 evaluable randomized patients, the CA-125 cumulative response rate was 53%. These results led the review panel to conclude that the trial should continue without protocol revisions.

Antibody-drug conjugates (ADCs) in ovarian cancer are being watched with interest due to the phase 1b/2 FORWARD II trial (NCT02606305), for which interim results for 1 cohort were presented at ASCO 2020.12 In the ongoing study, patients with folate receptor alpha (FRα)-positive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers are treated with the FRα/tubulin-targeting ADC mirvetuximab soravtansine in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, or pembrolizumab. In addition, a triplet of mirvetuximab plus carboplatin and bevacizumab is being tested in patients with FRα-positive platinum-sensitive ovarian cancer.

Preliminary data were presented for the mirvetuximab soravtansine/bevacizumab cohort, which enrolled 60 patients with FRα-positive, platinum-agnostic, recurrent ovarian cancer with a median 2 prior lines of therapy. In the overall patient population, objective responses were seen in 26 patients, for a confirmed ORR of 43% (95% CI, 31%-57%). In 33 patients with high FRα expression, the confirmed ORR was 61% (95% CI, 42%-77%), with an ORR of at least 50% in each of the platinum-resistant and platinum-sensitive subgroups.

For his part, Monk predicts that the most immediate potential for clarity for clinicians is likely to come when results are reported for the IMagyn050 trial evaluating the addition of atezolizumab to a bevacizumab/platinum chemotherapy combination in patients with newly diagnosed stage III or IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03038100).

“Adding immunotherapy to chemotherapy is a validated paradigm despite what the trials JAVELIN 100 [NCT02718417] and JAVELIN 200 [NCT02580058] told us,” he said. “This is already a big year in ovarian cancer, and if IMagyn050, which will report in the very near future, [shows] that atezolizumab and bevacizumab [is] impactful, that’ll really be game changing for us.”

As for Westin, she knows that having too many treatment options is a good problem to have. “But now we need to start thinking about how we can use this information to select the right drug for our patient who’s sitting in front of us in the clinic. PARP inhibitors are clearly here to stay, but there’s an opportunity to get better benefit for a certain population,” she says. “We’ll be focusing now on what to do with the patient population with HRD-positive [tumors] to see if some of these combinations will give better benefits than what we see with just PARP inhibitors alone. It will become increasingly important to test patients’ tumors so we can make the right choice as new therapies and combinations become available.”

1. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. May 8, 2020. Accessed July 7, 2020. bit.ly/2O5iw9K

2. Ray‑Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

3. Liu JF, Brady MF, Matulonis UA, et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. 

. 2020;38(suppl 15):6003. doi:10.1200/JCO.2020.38.15_suppl.6003

4. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed July 7, 2020. bit.ly/3gCtiR6

5. González‑Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. 

. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

6. Matulonis UA, Shapira R, Santin A, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. 

. 2020;38(suppl 15):6005. doi:10.1200/JCO.2020.38.15_suppl.6005

7. Matulonis UA, Shapira R, Santin A, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study. 

. 2018;36(suppl 15):5511. doi:10.1200/JCO.2018.36.15_suppl.5511

8. Westin SN, Lee S, Zhao L, et al. Pharmacodynamic changes by durvalumab in combination with chemotherapy in women with untreated, advanced stage ovarian cancer. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I; June 22-24, 2020. Abstract CT188.

9. Kimmons L. AACR: ovarian cancer clinical trial shows effects, safety of upfront immunotherapy and chemotherapy for advanced disease. MD Anderson Cancer Center. April 27, 2020. Accessed July 7, 2020. bit.ly/2BMBsHM

10. Rocconi RP, Stevens EE, Bottsford-Miller JN, et al. A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients. 

. 2020;38(suppl 15):3002. doi:10.1200/JCO.2020.38.15_suppl.3002

11. Arend RC, Monk BJ, Burger RA, et al. Clinical trial in progress: pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018). 

. 2020;38(suppl 15):TPS6097.doi:10.1200/JCO.2020.38.15_suppl.TPS6097

12. Gilbert L, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer. 

. 2020;38(suppl 15):6004. doi:10.1200/JCO.2020.38.15_suppl.6004

13. ImmunoGen announces initial data from FORWARD II study evaluating mirvetuximab soravtansine in combination with Avastin® in recurrent ovarian cancer, regardless of platinum status. News release. ImmunoGen. May 13, 2020. Accessed July 7, 2020. bit.ly/2BMoBFu

“What we’re trying to do is move toward more personalized precision medicine based on what actually happens inside the tumor."

Moving Toward Personalized Medicine, Immunotherapy Gains Foothold in Ovarian Cancer

Four cycles of R-CHOP (Rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) alone should be the new standard approach to limited-stage disease for the majority of patients with diffuse large B-cell lymphoma (DLBCL). That’s the conclusion of a new 

study that used positron emission tomography (PET)–directed treatment approaches to assess the outcomes and toxicity associated with the current standard of care.

A total of 158 patients were enrolled in the study and of those patients, 132 were eligible and 128 underwent interim PET scans after completing 3 cycles of R-CHOP. Only 14 patients (11%) had a positive PET scan; they then received radiation therapy per protocol. With a median follow-up of 4.92 years (range, 1.1 - 7.7 years), only 6 patients experienced progressive disease and only 3 patients died of lymphoma. Eleven patients died of unrelated causes during follow-up at a median age of 80 years. The 5-year progression-free survival (PFS) estimate was 87% (95% Confidence Interval [CI], 79% - 92%) and the overall survival (OS) estimate was 89% (95% CI, 82% - 94%). Patient outcomes were similar regardless of whether their PET scan was positive or negative.

“Together with the FLYER results in younger, more favorable-risk patients, the findings of our study have established that R-CHOP x 4 is a new standard, less morbid approach in limited-stage DLBCL for the absolute majority of patients, reserving radiation for the small subset of patients with interim PET-positive disease,” wrote the authors, led by Daniel O. Persky, MD, of the University of Arizona, Tucson, AZ. “The results were also favorable in subgroups defined by age, smIPI, cell of origin, and histology and were marginally unfavorable for DPE.”

S1001 (NCT01359592) was a phase II study for previously untreated patients with non-bulky (< 10 cm) stage I/II CD20-positive DLBCL. S1001’s primary end point was the 5-year PFS rate. Secondary end points included 5-year OS. Patients needed a WHO performance status of 0-2, adequate organ function, a normal left ventricular ejection fraction, and a negative bone marrow biopsy to enroll.

Patients received 3 cycles of standard R-CHOP treatment given every 3 weeks, with rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2

IV, vincristine 1.4 mg/m2 IV, and oral prednisone 100 mg for 5 days. Patients had an interim PET between day 15 and 18 of cycle 3 for central review. Patients whose PET scans were negative, defined as Deauville 1-3, then received 1 additional cycle of R-CHOP.

Patients whose PET was positive (Deauville 4-5) then received 36 Gy of involved field radiation therapy (IFRT), plus an additional boost to fluorodeoxyglucose (FDG)-avid areas of up to 9 Gy, within 5 weeks of cycle 3. Within 6 weeks after completing IFRT, patients received ibritumomab tiuxetan (Zevalin), with rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, and ibritumomab tiuxetan 0.4 mCi/kg on day 7, 8, or 9, after rituximab.

Of 128 patients whose interim PET scan received central review, 110 were negative. Of 18 patients with positive scans, 4 had infections and were treated as negative with 1 additional cycle of R-CHOP. Of the 14 patients whose scans were truly positive, 12 received IFRT followed by ibritumomab tiuxetan. Two-thirds of these patients (n = 8) converted from partial response (PR) to complete response (CR) after this additional treatment. Overall, CR was 92%, PR was 4%, and stable disease (SD) was 1%. 

Persky et al reported that 1 patient died of sepsis and 1 of hypoxia. Additionally, 13 patients (10%) had febrile neutropenia, and nearly one-third of patients (n = 57, 31%) had grade 3-4 neutropenia. Ten patients each (8%) had grade 3 anemia and grade 3-4 thrombocytopenia. Of the 12 patients who received IFRT followed by ibritumomab tiuxetan, 2 had grade 3-4 neutropenia, 3 had grade 3-4 thrombocytopenia, and 2 experienced radiation dermatitis.

The authors note that, of the 6 patients who progressed, 4 had negative interim PET and then received R-CHOP x 4. One patient with positive PET declined radiation, and 1 went off treatment after 1 cycle of R-CHOP because of treatment delay. No patients had primary refractory disease. The median time to progression was 1.1 years (range, 0.2 - 6.2 years), with a continuous pattern of relapse.

Given the relatively long follow-up, Persky et al observed several non-lymphoma deaths, particularly in older patients. “Indeed, our observed 5-year PFS rate of 87% did not meet our original goal of 93%, primarily because of the competing risk of death as a result of non-lymphoma causes (12.8% at 5 years) occurring in patients at a median age of 80 years,” they wrote. “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.”

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. 

Four cycles of R-CHOP alone should be the new standard approach to limited-stage disease for the majority of patients with diffuse large B-cell lymphoma. That’s the conclusion of a new study that used positron emission tomography–directed treatment approaches to assess the outcomes and toxicity associated with the current standard of care.

R-CHOP Alone Should Be New Standard in Early-Stage DLBCL, Researchers Say

Lenvatinib (Lenvima) offers potential benefits for patients with advanced hepatocellular carcinoma (HCC) with second- or later-line therapies and a high burden of intrahepatic lesions. These are the findings from a new study that set out to verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced HCC in real-world practice. The study, which was published in 

, focused mainly on the patient population that had been excluded from the REFLECT trial.

Of 152 advanced HCC patients, 95 patients (62%) received lenvatinib as first-line therapy, while 57 patients (38%) received the drug as second- or later-line systemic therapy. Child-Pugh class A patients experienced comparable median progression-free survival (PFS), regardless of whether they received lenvatinib as a first- or later-line therapy (First line median PFS: 5.2 months, 95% Confidence Interval [CI] 3.7–6.9; later-line median PFS: 4.8 months, 95% CI 3.8–5.9; 

Among patients with a high baseline burden of intrahepatic lesions (n = 27, 18%), the objective response rate (ORR) was 41%, a similar ORR to other trial populations.

The Child-Pugh class B population (n = 20, 13%) showed high-frequency rates of liver function-related adverse events (AEs) due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin–bilirubin (ALBI) scores.

“Lenvatinib is expected to be promising and beneficial for patients with advanced HCC requiring second- or later-line therapy and who have a high burden of intrahepatic lesions [but] we cannot recommend lenvatinib for Child-Pugh class B patients on the basis of the results of the present study,” wrote the authors, led by Susumu Maruta, MD, of Chiba University, Chiba, Japan. “Since lenvatinib may be an unexpectedly sensitive drug affected by liver function, more attentive management of lenvatinib dose modification should be considered.”

REFLECT was a phase III randomized open-label noninferiority trial conducted in 20 countries that compared lenvatinib to sorafenib (Nexavar) in first-line treatment of patients with unresectable HCC. Among 954 patients randomized to lenvatinib (n = 478) or sorafenib (n = 476), the median overall survival (OS) for lenvatinib was 13.6 months (95% CI, 12.1–14.9). The median OS for sorafenib was 12.3 months (95% CI, 10.4–13.9; hazard ratio [HR] 0.92, 95% CI 0.79–1.06), which met the authors’ predetermined criteria for noninferiority.2

The present study, which was conducted at 7 institutions in Japan, included mainly patients with Child-Pugh class A status. The authors specifically included patients with Child-Pugh class B status upon physician approval: “According to baseline radiological assessments, 27 patients (18%) had main portal vein and/or bile duct invasion or 50% or higher liver occupation by an intrahepatic tumor and conflicted with the radiological exclusion criteria of the REFLECT trial.” They defined this population as the “high burden of intrahepatic lesions” group.

Patients’ median age was 73 years old and nearly all patients had an ECOG performance status of 0 or 1 (93%). At 45%, hepatitis C virus was the most common etiology, followed by alcohol abuse (25%) and hepatitis B virus (13%). At baseline, 23% of patients had macrovascular invasion, while 38% of patients had extrahepatic metastasis.

The median PFS was 5.1 months (95% CI 4.4–5.9 months), while the median OS was 13.3 months (95% CI, 9.9–16.7 months). The median duration of treatment with lenvatinib was 5.3 months (95% CI, 4.5–6.1 months). The median observation period was 6.7 months (95% CI, 6.2–7.3 months), by the end of which 95 patients (62%) had discontinued lenvatinib. Disease progression was the most common reason for discontinuation at 38% (n = 58), while AEs were the next most common at 21% (n = 32). 

The most common AEs were hypothyroidism and anorexia (n = 63, 41% each). The most common grade 3 or higher AE were hypertension (n = 11, 7%), elevated aspartate transaminase (AST; n = 11, 7%), and proteinuria (n = 10, 6%). During follow-up, nearly 80% of patients (n = 120, 79%) required lenvatinib dose reductions due to AEs. The three most common causes of dose reductions were anorexia (n = 33, 22%), fatigue (n = 24, 16%), and encephalopathy (n = 18, 12%).

Maruta et al note that the incidence of HCC is expected to dramatically increase in upcoming decades, especially in East and South Asia. They remain hopeful that lenvatinib may be a promising agent for use in patients with advanced HCC with a high burden of intrahepatic lesions. “Although our study included a [lower] number of patients with advanced HCC with a high burden of intrahepatic lesions, further prospective or large cohort retrospective studies should be required to confirm the safety and efficacy of lenvatinib in this group,” they wrote.

1. Maruta S, Ogasawara S, Ooka Y, et al. Potential of Lenvatinib for an Expanded

Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma. 

. Published online May 5, 2020. DOI: 10.1159/000507022

2. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. Published online February 9, 2018. doi:10.1016/S0140-6736(18)30207-1.

Lenvatinib may benefit patients with advanced hepatocellular carcinoma with second- or later-line therapies and a high burden of intrahepatic lesions. 

Author | Darcy Lewis

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