Targeted Oncology is actively following as the COVID-19 pandemic develops.

COVID-19 Coverage

Robert Alter, MD, describes the rationale for treating a 58-year-old male with advanced renal cell carcinoma with the combination of lenvatinib and everolimus following progression on first-line therapy.

Case Perspective: Advanced RCC

In this episode of Targeted Talks, experts discuss the importance of precision medicine in breast cancer, and how that vitally differs in community oncology compared with academic settings.

Breast Cancer Leans into the Decade of ADCs

Atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel continues to prolong progression-free and overall survival in EGFR-mutant NSCLC.

IMpower150 Update Shows Continued Survival Benefit

Better response in survival were observed in patients with Child-Pugh B cirrhosis, a patient population that has limited treatment options, when given cabozantinib (Cabometyx). These patients are often underrepresented in clinical trials and have worse outcomes in overall survival (OS) and adverse events (AEs) compared with their Child-Pugh A counterparts.

“There [are] limited prospective data about the safety and efficacy of various systemic therapies in patients with advanced HCC and Child-Pugh B cirrhosis,” Anthony B. El-Khoueiry, MD, said in his presentation at the International Liver Cancer Association 2020 Virtual Conference. "The Child-Pugh B population is quite heterogenous and generally has [a] poorer prognosis than patients with Child-Pugh A.” According to the data from a retrospective exploratory analysis, patients with HCC and Child-Pugh B liver function in the CELESTIAL trial (NCT01908426) experienced clinical benefit in terms of OS and progression-free survival (PFS) hazard ratios and a manageable safety profile when receiving cabozantinib by week 8.2 

El-Khoueiry, an associate professor of clinical medicine in the Division of Medical Oncology at the Keck School of Medicine of the University of Southern California in Los Angeles, briefly recounted the phase 3 CELESTIAL study of patients with advanced HCC who were previously treated for their disease.3 The trial demonstrated that cabozantinib improved OS and PFS compared with placebo in these patients.


Patients with Child-Pugh B had an 8.5-month median OS on cabozantinib (95% CI, 7.7-12.2) versus 3.8 months on placebo (95% CI, 3.3-4.8), with a hazard ratio of 0.32 (95% CI, 0.18-0.58). The overall population had a median OS of 10.2 months and 8.0 months for cabozantinib compared with placebo, respectively (

“Similarly, when we look at PFS in the Child-Pugh B subgroup, cabozantinib resulted in a median PFS of 3.7 months versus 1.9 with placebo and a hazard ratio of 0.44 [95% CI, 0.25-0.76],” El-Khoueiry said. The overall population had a median PFS of 5.2 months on cabozantinib and 1.9 months on placebo, with the same hazard ratio as those in the subgroup (

Sixty-one percent of patients in the Child-Pugh B subgroup required a reduction in cabozantinib, which was comparable to the rate of the overall population at 62%, as well as discontinuations due to treatment-related AEs in 18% and 16%, respectively. The all-causality grade 3/4 AEs were alike, at 71% and 68%.

In the cabozantinib arm, 51 of 470 patients had investigator-assessed Child-Pugh B cirrhosis and 22 of 237 patients in the placebo arm had advanced to Child-Pugh B at week 8. 

"The breakdown at study entry was that 75% of patients had Child-Pugh A6 and 25% had A5. The deterioration from Child-Pugh A to Child-Pugh B at week 8 was mostly related to changes from baseline in albumin, bilirubin, and ascites [TABLE 2 ],” El-Khoueiry explained.

Patients in the Child-Pugh B subgroup receiving cabozantinib had higher rates of macrovascular invasion, which was present in 43% of patients compared with 32% of those on placebo and 27% in the overall population receiving cabozantinib, at baseline. Investigators also noted higher rates of extrahepatic spread of disease, which they observed in 82% of patients compared with 68% and 79%, respectively, and an elevated α-fetoprotein level—above 400 ng/mL—at 39% versus 27% and 41%.

In CELESTIAL, 760 patients with advanced HCC, Child-Pugh A score, an ECOG performance status of 0 or 1, and previous treatment with sorafenib (Nexavar) and up to 2 prior systemic regimens for their disease with progression following at least 1 of them, were randomized 2:1 to cabozantinib versus placebo.

The stratification factors were etiology—either hepatitis B virus or hepatitis C virus, both, or other—region, and presence of macrovascular invasion and/or extrahepatic spread. Patients randomized to cabozantinib were given 60 mg by mouth daily or placebo by mouth daily. Treatment was continued until loss of clinical benefit or intolerable toxicity. Additionally, crossover was not allowed on the study.

The primary end point of the trial was OS, and secondary end points included PFS, overall response rate, and safety. Investigators performed a tumor assessment every 8 weeks per RECIST 1.1 criteria. “Further prospective studies are warranted in Child-Pugh B patients with HCC, a population with considerable unmet need[s],” El-Khoueiry concluded.

1. Zhou K, Fountzilas C. Outcomes and quality of life of systemic therapy in advanced hepatocellular carcinoma. Cancers (Basel). 2019;11(6):861. doi:10.3390/ cancers11060861 

2. El-Khoueiry AB, Meyer T, Cheng AL, et al. Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib versus placebo. Slides presented at: International Liver Cancer Association 2020 Virtual Conference; September 11-13, 2020. Abstract 0-24. 

3. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. 

Articles

Better response in survival were observed in patients with Child-Pugh B cirrhosis, a patient population that has limited treatment options, when given cabozantinib in the phase 3 CELESTIAL study.

Patients With ChildPugh B Benefit From Cabozantinib in HCC

A New Drug Application (NDA) for pacritinib is planned to be submitted for potential accelerated approval from the FDA for the treatment of patients with myelofibrosis and severe thrombocytopenia, defined as platelet count less than 50 x 109/L, announced CTI BioPharma Corp. in a press release.

The NDA will be based on the findings from the phase 3 PERSIST-1 and PERSIST-2 clinical trial, as well as data from the phase 2 PAC203 dose-ranging study. Following agreement with the FDA, a rolling submission of the NDA is expected to commence in the next few weeks. Completion of the NDA is expected by the first quarter of 2021.

"Since the completion of the PAC203 phase 2 dose-ranging trial, we have been working collaboratively with the FDA to identify an expeditious approval pathway for pacritinib in myelofibrosis patients with severe thrombocytopenia, a patient population with an important unmet medical need due to reduced survival and limited therapeutic options. During a recent Pre-NDA meeting, we identified a data package from the PERSIST-1, PERSIST-2 and PAC203 phase 2 trials that will serve as the basis for an accelerated approval application. In particular, we discussed risk mitigation measures to address the FDA's prior concerns regarding safety," said Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma, in a statement.

The ongoing, randomized phase 3 PACIFICA study (NCT03165734) is expected to complete as a post-marketing commitment. This study is exploring the efficacy of pacritinib compared with the physician’s choice of therapy as treatment of patients with myelofibrosis and severe thrombocytopenia. Approximately 348 patients will be enrolled to the study and randomized to treatment 2:1.

The primary end point of PACIFICA is spleen volume, and secondary end points include total symptom score, overall survival, patient global impression of change, and safety of pacritinib compared with the physician’s choice of therapy. To be included in the study, patients must have an average platelet count of <50,000/µL at baseline, a DIPSS Intermediate-1, -2, or High-risk disease, and palpable splenomegaly ≥5 cm below the lower costal margin in the midclavicular line. Patients have to have an ECOG performance status of 0, 1, or 2 to be enrolled, as well as peripheral blast count of <10% and an absolute neutrophil count of ≥500/µL.

Patients with a life expectancy of <6 months, received prior allogeneic stem cell transplant or are eligible, have a history of splenectomy or plans to undergo 1, splenic irradiation within the last 6 months, and prior treatment with pacritinib. Patients are also ineligible if they have known human immunodeficiency virus or hepatitis A, B, or C virus.

“In myelofibrosis patients, severe thrombocytopenia occurs as a result of disease or drug-related toxicity from current therapies. There is no approved drug that specifically addresses the unmet need of the myelofibrosis patients who have severe thrombocytopenia,” stated Craig. “Pacritinib has demonstrated clinical benefit in treating these patients in multiple trials and now has the potential to become a new treatment option for treatment-naïve and second-line myelofibrosis patients in 2021.”

Pacritinib is an oral investigational kinase inhibitor that is specific for 

. These kinase mutations are associated with the development of blood-related cancers, such as myeloproliferative neoplasms. Pacritinib previously received a Fast Track designation in 2014 for the treatment of patients with intermediate- and high-risk myelofibrosis, including patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy, or patients intolerant of or whose symptoms are not well controlled on other JAK2 therapy.

CTI biopharma to submit a new drug application (nda) for the accelerated approval of pacritinib for the treatment of myelofibrosis patients with severe thrombocytopenia. News Release. CTI BioPharma Corp. September 29, 2020. Accessed September 30, 2020. https://bit.ly/34jniZ4

A New Drug Application for pacritinib is planned to be submitted for potential accelerated approval from the FDA for the treatment of patients with myelofibrosis and severe thrombocytopenia.

New Drug Application Planned for Submission to FDA for Pacritinib in Myelofibrosis

Pennsylvania Society of Oncology & Hematology Welcomes Arturo Loiaza-Bonilla, MD, MSEd, as New President

Harrisburg, PA – Dr. Arturo Loaiza-Bonilla, MD, MSEd ascended to the presidency of the Pennsylvania Society of Oncology, albeit virtually, during the society’s Annual Scientific Conference held via ZOOM on September 25.

The Vice Chief of Medical Oncology for the Cancer Treatment Centers of American and its Medical Director of Research at CTCA Philadelphia, Dr. Loaiza-Bonilla completed his undergraduate degree and medical degree at Universidad Nacional de Colombia in Bogata, Columbia. An internship and residency in internal medicine followed at Johns Hopkins Harbor Hospital Center in Baltimore as did a fellowship in hematology and oncology at the University of Miami’s Miller School of Medicine and University of Miami’s Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital.

Prior to joining CTCA in 2017, Dr. Loaiza-Bonilla pursued a MSEd in medical education at the University of Pennsylvania while also serving as an assistant professor at the University’sPerelmen School of Medicine. He also co-founded Massive Bio, a global industry leader in connecting patients to clinical trials. He continues to serve as its Chief Medical Advisor.

Board certified in medical oncology and hematology, Dr. Loaiza-Bonilla is an internationally renowned medical oncologist and researcher, having been published in numerous medical journals and oncology publications including ASCO’s Clinical Journal of Oncology and Google Scholar. He is a reviewer and counselor for several journals, special interest groups, panels and academic competitions and a principal investigator and co-investigator for many large oncology clinical trials.

In addition to the Pennsylvania Society of Oncology and Hematology, Dr. Loaiza-Bonilla has been a member and leader in the American Society of Hematology, American Society of Clinical Oncology and American Association of Cancer Research.

As president of PSOH, Dr. Loaiza-Bonilla intends to devote his two-year term to strengthening the organization as a resource, educator, and advocate for the oncology and hematology community.

The Pennsylvania Society of Oncology and Hematology is an organization of physicians and health care professionals devoted to the improvement of hematologic and oncologic care of patients since 1998. It strives to educate physicians and cancer care professionals about the latest clinical advances in cancer diagnosis, care and cancer-related issues; to set standards and guidelines for diagnosis and care of patients with hematologic and oncologic disorders; and to provide nonpartisan, multidisciplinary expert input to governmental bodies, legislators, third-party payers and other appropriate parties.

Rana R. McKay, MD, associate professor of Medicine and medical oncologist at the University of California, San Diego, discusses the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) versus sunitinib (Sutent) in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC).

The top-line data from the CheckMate 9ER study (NCT03141177) showed this combination induced a statistically significant improvement in radiographic progression-free survival (rPFS), overall survival (OS), and objective response rate (ORR) compared with sunitinib for these patients. The median rPFS by independent radiology review, which was the primary end point of the trial, was 16.6 months with the combination versus 8.3 months in the control arm, with a hazard ratio of 0.51. McKay says the investigator assessment of rPFS was similar, with 19.4 months versus 9.2 months for the combination versus sunitinib, respectively, and a hazard ratio of 0.46.

There was a statistically significant OS improvement as well. Although the medians have not been reached, the hazard ratio was 0.60. For the ORR, there was a statistically significant improvement, with an ORR of 55.7% with nivolumab and cabozantinib versus 27.1% with sunitinib. The complete response rate with the combination was 8%. The median time to response was also improved at 2.8 months, and the duration of response was close to 2 years with nivolumab and cabozantinib, according to McKay.

McKay says this trial enrolled a larger percentage of patients with RCC who had their primaries intact, at 30%, and 15% of patients with bone metastases.

<< View more regarding renal cell carcinoma

Videos

Rana R. McKay, MD, discusses the combination of nivolumab and cabozantinib versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma. 

CheckMate 9ER Trial Demonstrates Efficacy in Patients With RCC

Cyrus M. Khan, MD, a hematologist/oncologist, at Allegheny Health Network in Pittsburgh, PA, discussed the case of a 61-year-old patient with bone marrow biopsy confirmed chronic lymphocytic leukemia (CLL). 

Is molecular testing for CD38 and Zap-70 still used in a prognostic panel?

Not any more. It used to be there, but now it’s supplanted by all the newer testing that we have, such as IgH3 status, and then del(17p), del(11q). Sometimes del(13q) even gives you a better prognosis. So those are more commonly done now.

Do you usually do a routine bone marrow biopsy for patients?

Not always. At diagnosis, it’s rare that you get a flow cytometry that’s [uncertain], and I have only had 2 or 3 patients over the last year where the flow cytometry said it was CLL, but I was concerned because it was unusual, and then when we did the eventual bone marrow [biopsy] and further testing, it turned out to be the leukemic variety of mantle cell lymphoma. You can be confused sometimes—so I do not always [do a bone marrow biopsy].

What do you think of the answers in the polling question about optimal therapy for this patient?

I see 33% [of participants] chose ibrutinib [Imbruvica], about 25% chose ibrutinib plus monoclonal antibody, 16% chose 

acalabrutinib [Calquence], 25% chose venetoclax [Venclexta] plus monoclonal antibody, and none chose chemoimmunotherapy.

[Ibrutinib is] a great choice. It’s the first BTK [Bruton tyrosine kinase] inhibitor that came on the market, and it works well. We have realized [this] over many years [and] a lot of long-term data. And so a lot of people are familiar with it.

One of the benefits of using [venetoclax plus an anti-CD20 monoclonal antibody] approach would be finite duration of therapy. Any BTK inhibitors we use, you have to continue the treatment until progression or toxicity. With venetoclax plus an anti-CD20 antibody, at least it’s time defined and you can stop therapy at a certain point.

How do the National Comprehensive Cancer Network (NCCN) guidelines suggest treating these patients?

The NCCN tells us for patients who are unable to tolerate chemotherapy, are above 65 years, or have significant comorbidities, the preferred agents are all the novel therapies.1 It’s ibrutinib, acalabrutinib plus/minus obinutuzumab [Gazyva], and venetoclax plus obinutuzumab.

There are other frontline therapies, depending on what category of evidence we have. For patients who are younger, less than 65 years, the preferred agents are novel therapies.

We have almost 6 to 7 years’ worth of data with the BTK inhibitors. We have BCL2 inhibitors, and a lot of head-to-head comparisons have been done.

What are the data supporting acalabrutinib in this setting?

The acalabrutinib data come from the phase 3 ELEVATE treatment-naïve [TN] study [NCT02475681].2 This was in 535 patients; they had to be either above 65 years or below 65 years with comorbid conditions. They were randomized into 1:1:1 to acalabrutinib plus obinutuzumab [or acalabrutinib monotherapy or obinutuzumab/chlorambucil].

Crossover was allowed from obinutuzumab plus chlorambucil to acalabrutinib monotherapy if the patient had progression. Off the bat, we know that the overall survival [OS] might eventually not be that different because crossover is allowed.

Which regimens did the best in the ELEVATE TN trial?

As far as the progression-free survival [PFS] is concerned, obinutuzumab plus chlorambucil showed a median PFS of almost 2 years. When we look at acalabrutinib monotherapy, median PFS has not been reached at 28.3 months. The same goes for acalabrutinib plus obinutuzumab.

Almost all the patients [by subgroup] did better with the acalabrutinib approach, whether it’s monotherapy or with obinutuzumab. It doesn’t matter [about] the age or if there’s palliative disease; most of the patients do better. Whether it’s the mutational status del(11q), del(17p) or not, everyone favored an acalabrutinib approach.

I think a deep response is needed if you’re going to do a finite therapy. But with BTK inhibitor use, we’ve noticed that even if you don’t get a complete response or a deep response, the longer you use these BTK inhibitors, the deeper the responses get. But if you are somebody who takes into account the response rates, acalabrutinib and obinutuzumab had the greatest response rate at 94% and complete response of 13%. Acalabrutinib monotherapy had about 85% response rate and chlorambucil/obinutuzumab had about 79% response rate.

OS was similar [for all 3 cohorts]. CLL is a disease that’s indolent, unless it’s high risk, so you need follow-up for many years if you’re going to realize any OS difference. Also, when patients progress, they can be retreated with good options. This is a crossover design, so we’re not going to see a lot of differences in the future.

As far as safety is concerned, about 12 patients had pneumonia on acalabrutinib plus obinutuzumab, and 5 patients on acalabrutinib monotherapy. There was some anemia, but overall low numbers. Febrile neutropenia was observed in 3 patients versus 2 patients, respectively. So these were low numbers and well tolerated. I’m sure this reflects the practice of those who have used the drug.

When you look at toxicities that are specific to BTK inhibitors, only 1 patient had atrial fibrilation [AF] of grade 3. Six patients had it of any grade. There was hypertension also developing over time; 5 patients had grade 3 hypertension. Major bleeding was seen in only 3 patients—1.7% in acalabrutinib plus obinutuzumab, and similarly low numbers with acalabrutinib monotherapy. Infections are part and parcel of CLL, unfortunately, because it’s an immune dysregulation with CLL, especially in the relapsed setting. That was seen in 20.8% at grade 3 with acalabrutinib plus obinutuzumab.

What other regimens are relevant for this patient?

Ibrutinib has been around for many years. The phase 3 RESONATE-2 trial [NCT01722487] looked at frontline ibrutinib for CLL.3 There were 269 patients either above 65 years or who had some comorbidities. Patients with del(17p) were excluded. They were randomized to ibrutinib 420 mg daily until progression or toxicity versus chlorambucil, which we’ve had for many years. That was the comparator many years ago. This was a crossover design, so 55 patients did cross over.

At 18-month follow-up, there was a big difference in the PFS between ibrutinib and chlorambucil [not reached vs 18.9 months; HR, 0.16; 

<.001]. But we also have 5-year data. The median PFS still has not been reached, and chlorambucil [had a median PFS of 15 months; HR, 0.146].

The subgroup analysis showed del(11q), [which] is a bad prognostic marker. But if you use ibrutinib with del(11q) compared with ibrutinib without del(11q), it’s similar. When you use a chemotherapy approach [such as] chlorambucil, patients don’t do as well, and the patients with del(11q) do even worse.

status, patients with unmutated or mutated 

had similar [responses]. If you use chlorambucil, the patients with unmutated 

Please describe the more recent data for this setting.

There are newer data, with the ECOG E1912 trial [NCT02048813].4 This was a groundbreaking trial because the 

idea was to see whether ibrutinib was better than FCR [fludarabine, cyclophosphamide, and rituximab], which has been the gold standard for many years. E1912 had new patients, previously untreated CLL, young patients [who were] able to tolerate FCR, because not everybody can do that. There were no patients with del(17p). Arm A was ibrutinib plus rituximab. Generally, rituximab was continued for 6 cycles, and then ibrutinib was continued until progression or toxicity. FCR was the standard 6 cycles, and for rituximab, the dosing was different.

The PFS at 48 months [showed] ibrutinib plus rituximab looked better. This was statistically significant [HR, 0.39; 95% CI, 0.26- 0.57; 

<.0001]. OS was similar, so we’ll have to see how this pans out. But for now, it’s statistically significant; ibrutinib had 4 deaths, and chemotherapy had 10 deaths [HR, 0.17; 95% CI, 0.05-0.54; 

What are the data for treating patients with venetoclax?

The newest treatment on the block is the CLL14 trial [NCT02242942], which looked at obinutuzumab plus venetoclax versus chlorambucil and obinutuzumab in patients with previously untreated CLL.5 This was in the front line; they had to be patients unfit for chemoimmunotherapy. Obinutuzumab was 6 cycles, and venetoclax was [given for] 1 year. With chlorambucil and obinutuzumab, obinutuzumab was for 6 cycles and chlorambucil for 12 cycles. This was a randomized phase 3 clinical trial.

With a median follow-up of 28 months, venetoclax plus obinutuzumab—even though it was stopped at 12 months—still showed PFS superiority over chlorambucil and obinutuzumab, at 88% versus 64%, respectively. Even at 40 months, for venetoclax plus obinutuzumab, the median PFS had not been reached; this is statistically significant [HR, 0.31; 95% CI, 0.22-0.44; 

As far as mutational status is concerned, if a patient’s disease is mutated, they do well [with venetoclax]. If [their disease is] unmutated, they do equally well, but there was a slight drop-off later on. The difference is even wider if you’re using chlorambucil and obinutuzumab.

The more interesting part is del(17p). The patients without 

mutations do well with venetoclax. There was a drop [after a while], so we have an idea that patients with del(17p) do poorly no matter what you do.

Looking at minimal residual disease [MRD], there’s low MRD negative, medium, and then there’s high MRD negative. We have many things showing that if your patient does achieve MRD-negative status with chemotherapy or these time-defined treatments, that does show that the PFS is longer. Even with this all-novel approach without chemotherapy, undetectable MRD was seen in the peripheral blood in 76% of the patients with venetoclax plus obinutuzumab. So two-thirds had MRD-negative status. If it was checked in the bone marrow, almost half the patients had undetectable MRD. Not as many patients had it with chlorambucil and obinutuzumab. This was checked 3 months after completion of treatment. It was the monoclonal antibody treatment that this was checked in. At 9 months, MRD was checked, and then at the end of treatment, as well.

These are important data. Even if you stop treatment at 12 months, [patients with undetectable MRD were] doing well. But later on, with venetoclax plus obinutuzumab and undetectable MRD, [patients] continue to do well. On chlorambucil and obinutuzumab, even if patients are undetectable, they drop off quickly.

In patients receiving venetoclax/obinutuzumab, if they’re MRD positive before they stop, the drop-off [in efficacy] starts happening. Unfortunately, if you can’t get a quick response, it doesn’t matter whether you stop or not; the drop-off continues.

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma; version 4.2020. Accessed August 25, 2020. http:// bit.ly/34vUU7s

2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. 

. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

3. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. 

. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x

4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. 

. 2019;381(5):432-443. doi:10.1056/ NEJMoa1817073

5. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. 

2019;380(23):2225‐2236. doi:10.1056/ NEJMoa1815281

Cyrus M. Khan, MD, discussed the case of a 61-year-old patient with bone marrow biopsy confirmed chronic lymphocytic leukemia during a Targeted Oncology Case Based Peer Perspectives event.

Khan Implements a Treatment Plan for a Patient With CLL

Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease in which efforts to individualize therapy remains limited. However, comprehensive multiplatform genomic analyses have sparked new knowledge that can be used to facilitate a major paradigm shift, allowing for the use of precision medicine-based approaches.

 was conducted to understand how precision medicine strategies can be successfully implemented in DLBCL, in which authors described recently proposed genomic categories of DLBCL and the potential ways to personalize treatment in these subgroups. Traditional classification tools used in DLBCL were examined, as well as prior unsuccessful efforts to personalize treatment based on the subtypes of disease.

About two-thirds of patients with DLBCL can experience prolonged survival outcomes with frontline chemoimmunotherapy, but the remaining population with relapsed/refractory disease are associated with poor outcomes. A variety of categorization systems are available to help understood the variability in sensitivity to this standard therapy, which is thought to be reflected in the underlying molecular heterogeneity of the disease.

The Issue With Frontline Chemoimmunotherapy

Initial studies evaluated the activate B-cell-like (ABC) and non-germinal center B-cell-like (GCB) subtypes of DLBCL. The proteasome inhibitor bortezomib (Velcade) was expected to overcome the poor prognosis associated with this population, but a randomized phase 2 study demonstrated no improvement with the addition of this agent to chemotherapy. The phase 3 REMoDL-B study also failed to show improvement in progression-free survival (PFS), regardless of cell-of-origin (COO) classification.

In this study, the 20-month PFS rate was 70.1% (95% CI, 65.0%-74.7%) with R-CHOP alone versus 74.3% (95% CI, 69.3%-78.7%) with the addition of bortezomib (HR, 0.86; 95% CI, 0.65-1.13; 

 =.28). There were no differences observed in PFS or overall survival for either GCB or ABC subtypes of DLBCL.

The addition of Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) was also evaluated in this patient population. Improved responses were observed in a phase 1/2 clinical trial that prompted development of the phase 3 PHOENIX study that compared ibrutinib in combination with R-CHOP to R-CHOP alone. However, there were no improvements in the event-free survival with the addition of ibrutinib (HR, 0.934; 95% CI, 0.726-1.200; 

 An exploratory analysis demonstrated a potential advantage of adding ibrutinib to R-CHOP in patients aged < 60 years and in those with DEL, but the benefit was not limited to those with true ABC disease.

Lenalidomide (Revlimid), an immunomodulatory drug, was also expected to have preferential activity in the ABC subgroup based on findings from preclinical models. The agent showed encouraging findings in a single-arm phase 2 study, but benefit was not observed when the agent was added to R-CHOP in the phase 3 randomized ROBUST clinical trial. However, there was no difference observed in PFS between the 2 arms (HR, 0.85; 95% CI, 0.63-1.14; 

 overexpression and gene rearrangements are under evaluation as well to determine potential targeted therapeutic approaches. The phase 1b/2 CAVALLI study evaluated the addition of the BCL-2 inhibitor venetoclax (Venclexta) to chemoimmunotherapy, in which the potential predictive impact of COO and DEL was explored. CAVALLI evaluated patients with high-risk disease and demonstrated a complete response rate of 69.2%, which was similar to the historical findings from the GOYA study. The outcomes appeared to improve compared with the historical data, but the improvement was not observed in COO tumors.

The findings from studies incorporating targeted therapy into the maintenance setting have been disappointing. For example, the PRELUDE study demonstrated no benefit with the addition of the PKCβ inhibitor enzastaurin (DB102) after R-CHOP therapy, regardless of COO subtype, and the PILLAR-2 study saw no benefit with the addition of everolimus (Afinitor) after completion of frontline therapy in patients with high-risk DLBCL defined by International Prognostic Index (IPI).

Overall, several large phase 3 studies have been conducted and failed to improve treatment with R-CHOP or failed to provide molecularly stratified therapies in DLBCL. This may be in part due to biased enrollment of healthier patients onto clinical trials. Many patients are excluded from patients due to their urgent need to initiate therapy, as well as the time required for trial screening. This leads to exclusion of many clinically aggressive cases in clinical trials, many of which have worse outcomes.

Another concern with these trials is the accuracy of COO classification by immunohistochemistry (IHC). The REMoDL-B study incorporated GEP for COO classification, but considering the challenge in incorporating molecular tools into patients urgently needing therapy, patients did not receive bortezomib treatment until cycle 2 after COO classification was determined. The PHOENIX trial potentially adopted a new solution, which was to enroll patients on the basis of IHC classification but perform GEP and retroactively analyze GEP classification results in prespecified analyses.

Molecular Classification Under Evaluation in DLBCL

IPI has been the most important and successful clinical risk stratification tool in DLBCL, according to the review. Several variants were derived from IPI, including the COO classification and various methods capturing double-hit lymphoma or related subtypes. However, despite its power and value as a reproducible model, it has not improved the stratification of patients as it does not align directly with the molecular heterogeneity of DLBCL. The genomic classification’s prognostic value is complementary to IPI but not sustainable.

The inventive application of gene expression profiling was the first major step toward understanding the genomic complexity of the disease by using hierarchical clustering algorithms on cDNA microarrays of tumors. Two principal subtypes were identified, which included the GCB and the ABC subtypes.

COO provides important prognostic information, but the Hans algorithm, which is based on a wieldier IHC platform, has become more broadly used. However, GEP remains the golden standard, whereas the sensitivity to IHC to assign COO is only ~70% for GCB and ~90% for non-GCB.

GEP technologies have advanced in recent years with the ability to use RNA from formalin-fixed paraffin-embedded tissue. These advancements have allowed for the development of assays that can be more reliably applied to patient samples. RNA-based approaches have become standard in assigning COO for research.

Another transcriptional profiling classification includes the comprehensive consensus clustering (CCC), which identified distinct variants of DLBCL. This is important for identifying distinctions in predominant field utilization pathways that are associated with either the presence or absence of B-cell receptor signaling and features of the tumor immune/inflammatory infiltrate. CCC identifies biologic heterogeneity in DLBCL similar to COO but has a more limited role in clinical practice currently. CCC has not yet been used to test individualized treatment approaches in DLBCL.

Deepening the Understanding of Genomics in DLBCL

Other biologic features that contribute to prognosis include 

 translocations, which tend to have unfavorable outcomes. Tumors harboring 

 translocations, which are known as the double- or triple-hit lymphomas, have been shown to be more chemotherapy-refractory, in which intensified regimens have been associated with better outcomes retrospectively. For example, dose-adjusted R-EPOCH is the preferred intensified regimen in most centers.

Intensified regimens, however, are not targeted therapies, but they represent 1 of the few examples of genomically-stratified therapy in patients with DLBCL. Most double-hit tumors are considered GCB, and efforts to distinguish the remainder of GCB DLBCLs with RNA sequencing has led to the recognition of a distinct molecular subgroup that is characterized by a double-hit signature.

A distinct subgroup was also identified in a GEP of a large DLBCL sample cohort with a molecular high-grade (MHG) profile, which was associated with a significantly worse PFS. Patients with double-hit lymphoma that do have the MHG signature had similar outcomes to those with GCB DLBCL. This suggests that chromosomal rearrangements could be used to identify the more aggressive variant.

Chemotherapy-refractoriness could be better predicted in DLBCL with more sophisticated tools, the authors wrote, which could improve selection of patients for intensified chemotherapy approaches today and more targeted therapies tomorrow.

The advancement of genomic characterization tools over the last decade has allowed for a deeper understanding of recurrent aberrations in DLBCL. For example, the COO transcriptional framework allows for identification of genetic alterations enriched in either GCB or ABC tumors. The inclusion of a broader range of genomic changes has also deepened this understanding considerably in conjunction with new computational tools, gene expression, and functional analyses.

One study conducted by the Harvard group used genomic information from 304 samples from newly diagnosed patients with DLBCL to create a novel classification system. The study included a range of genomic aberrations and classified tumors, which ultimately led to the identification of 5 genomic clusters with salient features.

Clusters 1 and 5 were significantly enriched for ABC tumors, whereas clusters 3 and 4 were enriched for GCB tumors. Significant prognostic differences were observed in each case, with inferior outcomes in patients with cluster 3 and 5 tumors. These findings demonstrate the significant genomic variability beyond the COO classification, which can help explain the variability of the prognostic impact of COO classification across studies. More importantly, these findings underscore the difficulty of using COO classification to select patients for targeted therapies.

 alterations occurred together the most commonly in cluster 3, 

translocations occurred most commonly in cluster 1, making this a biologically distinct group of patients from those in cluster 3, strengthening the idea that double-hit lymphomas may have prognostic relevance but not biologic homogeneity.

The National Cancer Institute (NCI) identified genes with recurrent aberrations among 574 samples from patients with DLBCL by using exome and transcriptome sequencing, array-based copy number analysis, and targeted amplicon resequencing. This analysis was layered onto the COO classification to define 4 distinct subgroups of DLBCL. The NCI more recently conducted an analysis to characterize the genomic underpinnings of these 4 subgroups more fully.

In this analysis, the most common mutation was 

, which was associated with high rates of aneuploidy. A fifth cluster was also defined in this analysis, which was termed A53 (aneuploid with TP53 inactivation). Another seed class was also created, the ST2, which includes 

 mutations. The DHITSig cluster was further stratified, defined by 

 aberrations into MYC+ and MYC– categories. Overall, the NCI was able to define 7 genomic subgroups, which can be used to provide a probabilistic classification of a tumor from an individual patient with DLBCL into a genetic subgroup.

The other novel genomic categories defined by the NCI are BN2, EZB, MCD, and NI. Key genomic characteristics in the BNq arm include alterations in NOTCH2 signaling, B-cell differentiation, regulators of NF-kB pathway, immune evasion or loss of CD70 loss, 

 SVs. EZB includes characteristics like alterations in epigenetic regulators, mutational activation of 

, alterations affecting B-cell signaling, inactivation of S1PR2/GN13 pathway, PTEN deletions and mutations, 

amplification, perturbed interactions with T follicular helper cells, MYC+ and MYC–.MCD includes mutations in 

 copy gain/amplification, and immune evasion. NI includes alterations in 

, mutations in B-0cell differentiation regulators, and 

Another study applied a targeted 293-gene panel to a large population-based cohort of 928 patients with DLBCL, in which 5 distinct molecular subgroups were also defined, termed MYD88, BCL2, TET2/SGK1, SOCS1/SGK1, and NOTCH2. About one-fourth of patients in this analysis failed to fall into 2 of these subgroup categories and were not classified. The subgroups of this study were generally similar to those described by both the NCI and Harvard groups.

The classifications found among these studies and others have important distinctions and nuances, providing a deep and broad understanding of the biology of DLBCL. However, the results of these studies appear broadly similar, and several subgroups identified across the studies have unmistakable resemblances to others. The overlapping conclusions of these studies support the presence of previously unrecognized distinct genomic subgroups with coordinate biology.

A more detailed genetic subclassification is expected to supersede the COO framework, or at least provide a finer way to assess prognosis in DLBCL. The promise of these studies is in their potential to successfully individualize therapy.

Novel classifications provide testable predictions for specific therapeutic vulnerabilities for select groups that can be tested in preclinical models. The goal of this research is to select treatment that selectively targets the vulnerabilities implied by a patient’s genomic classification and improve outcomes overall.

1. Crombie JL, Armand P. Diffuse large b-cell lymphoma’s new genomics: the bridge and the chasm. Published online August 19, 2020.

2. Davies A, Cummin TE, Barrans S, et al: Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): An open-label, randomised, phase 3 trial.

Oncol 20:649-662, 2019. doi: 10.1016/S1470-2045(18)30935-5

3. Younes A, Sehn LH, Johnson P, et al: Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma.

37:1285-1295, 2019. doi: 10.1200/JCO.18.02403.

4. Vitolo U, Witzig TE, Gascoyne RD, et al: ROBUST: First report of phase III randomized study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma.

5. Zelenetz AD, Salles G, Mason KD, et al: Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial.

133: 1964-1976, 2019. doi: 10.1182/blood-2018-11-880526.

6. Morschhauser F, Feugier P, Flinn IW, et al: Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) improves outcomes in BCL2-positive first-line diffuse large B-cell lymphoma (DLBCL): First safety, efficacy and biomarker analyses from the phase II CAVALLI study.

7. Chapuy B, Stewart C, Dunford AJ, et al: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

24:679-690, 2018. doi: 10.1038/s41591-018-0016-8.

8. Schmitz R, Wright GW, Huang DW, et al: Genetics and pathogenesis of diffuse large B-cell lymphoma.

Med 378:1396-1407, 2018. doi: 10.1056/NEJMoa1801445

A review was conducted to understand how precision medicine strategies can be successfully implemented in diffuse large B-cell lymphoma

Studies Must Refine Genomic Classification Tools to Improve Use of Targeted Therapies in DLBCL Subgroups

Atezolizumab (Tecentriq) in combination with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) demonstrated continued progression-free survival (PFS) and overall survival (OS) benefit at 20 months of follow-up compared with bevacizumab, carboplatin, and paclitaxel (BCP) in patients with chemotherapy-naïve metastatic nonsquamous non–small cell lung cancer (NSCLC) who harbor an 

 mutation, according to updated efficacy results from a sub-analysis the phase 3 IMpower150 clinical trial (NCT02366143).

IMpower150 was launched to address failure to tyrosine kinase inhibitors (TKIs), which are the recommended treatment option in the frontline setting. After failure on TKIs, the PFS achieved with these agents in the second- and later-line settings are significantly lower. Prior results from IMpower150 did demonstrate a survival benefit with an 8.3-month median PFS in the atezolizumab arm compared with 6.8 months in the control arm (95% CI, 0.52-0.74; 

 < .001). The initial results from the study led to the FDA approval of the regimen in patients with metastatic nonsquamous NSCLC with an 

In the randomized, open-label, international study, 1202 patients were randomized 1:1:1 to receive either ABCP, atezolizumab plus carboplatin and paclitaxel (ACP), or BCP every 3 weeks. Atezolizumab was administered at 1200 mg intravenously (IV), carboplatin AUC 6 was also administered IV, and was bevacizumab at 15 mg/kg. The dose level for paclitaxel was 200 mg/m2.

In the intention-to-treatment population in the subgroup analysis, 87% of patients had wild-type disease, 13% had an 

 mutation. Specifically, 10% in the mutated group were 

Across all subgroups explored in the study, patients with 

 mutations who were treated with ABCP had a median PFS of 10.2 months compared with 7.1 months in the BCP arm (HR, 0.56; 95% CI, 0.34-0.91). Among those with sensitizing 

 mutation, the median PFS was 10.3 months with ABCP compared with 6.1 months in the BCP arm (HR, 0.38; 95% CI, 0.21-0.68). Additionally, in the subset of 50 patients who received prior treatment with a TKI, the median PFS was 9.7 months in the ABCP group versus 6.1 months in the BCP group.

Comparing treatment with ACP versus BCP, the median PFS in patients with an 

 mutation was 6.9 months compared with 7.1 months, respectively (HR, 0.93; 95% CI, 0.60-1.44). In the group of 65 patients with an 

 sensitizing mutation, the median PFS with ACP was 6.5 months versus 6.1 months with BCP (HR, 0.88; 95% CI, 0.53-1.47). The 56 patients who received prior TKI therapy had a median PFS of 5.7 months in the ACP arm versus 6.1 months in the BCP arm (HR, 1.24; 95% CI, 0.72-2.15).

OS in the intention-to-treat population favored ABCP compared with BCP in patients with an 

 mutation. The median OS was 20.3 months (95% CI, 13.4-33.6) in the ABCP arm versus 26.1 months (95% CI, 17.0 41.4) in the BCP arm (HR, 0.91; 95% CI, 053-1.59). The ACP arm was slightly inferior to the BCP arm in terms of OS though. The median OS was 20.3 months (95% CI, 13-4-33.6) in the ACP arm compared with 21.4 months (95% CI, 14.0-31.4) in the BCP arm (HR, 1.16; 95% CI, 0.71-1.89).

The BCP group demonstrated better OS than both ABCP and ACP among the subgroup of patients who had an 

 sensitizing mutation. The median OS was 18.1 months (95% CI, 11.7-27.8) in the ABCP arm compared with 29.4 months (95% CI, 24.9-not evaluable). In the BCP arm (HR, 0.60l 95% CI, 0.31-1.14). The median OS observed with ACP was 18.1 months (95% CI, 11.7-27.8) versus 19.0 months (95% CI, 13.5-28.5) with BCP (HR, 1.00; 95% CI, 0.57-1.74).

Finally, BCP had much longer OS compared with both ABCP and ACP among patients with sensitizing 

-positive disease who received prior treatment with a TKI. The median OS observed was 18.1 months (95% CI, 12.3-27.8) in the ABCP arm versus 27.8 months (95% CI, 18.6-41.4) in the BCP arm (HR, 0.74; 95% CI, 0.38-1.46). Treatment with ACP showed a median OS of 14.9 months (95% CI, 13.1-22.3) compared with 18.1 months (95% CI, 12.3-27.8) in the BCP arm (HR, 1.22; 955 CI, 0.68-2.22).

Objective responses were higher and the duration of response (DOR) longer in patients who were treated with ABCP compared with those who received BCP. The objective response rate (ORR) was 73.5% in the ABCP arm with a median DOR of 11.1 months (95% CI, 6.8-16.1) versus 40. (% with a median DOR of 4.7 (95% CI. 4.2-7.1) in the BCP arm, and 37.8% with a median DOR of 6.9 months (95% CI, 4.2-14.5) in the ACP arm. The difference between ABCP and BCP was demonstrated with a hazard ratio (HR) of 029 (95% CI, 0.14-0.58), and the difference between ACP and BCP was demonstrated with an HR of 0.47 (95% CI, 0.22-1.01). Notably, there was no change in the ORR following treatment with either ACP versus BCP, but there was a small increase in the DOR.

Overall, 44 patients from the ACP arm, 33 patients from the ABCP arm, and 43 patients from the BCP arm were evaluated for safety. Considering the longer follow-up in the BCP arm, these patients received more subsequent therapies that were unrelated to the study protocol. Specifically, 79.1% of the BCP received non-protocol treatment compared with 45.5% in the ABCP arm and 70.5% in the ACP arm. In addition, 27.3% of the ABCP arm and 43.2% of the ACP received targeted therapy, and 21.2%, and 18.2%, respectively were given post-progression osimertinib (Tagrisso).

The safety profile overall was consistent with each drug individually. Treatment was well-tolerated in the 

-positive population, despite a longer treatment duration. In all study arms, grade 3 o 4 treatment-related adverse events (AEs) were reported, including in 57% of the ACP arm, 67% of the ABCP arm, and 56% of the BCP arm. Only 1 patient in the BCP arm had a grade 5 AE. Serious AEs were reported in 36.4% of the ACO arm, 42.4% of the ABCP arm, and 20.9% of the BCP arm. Some patients withdrew from the study due to AEs, including 13.6 from the ACP arm, 42.4% from the ABCP arm, and 16.3% from the BCP arm.

Immune-related AEs were also reported in more than 5 patients. The most common in the ACP, ABCP, and BCP arms, respectively, were rash (36.4%, 33.3%, and 11.6%) hepatitis (6.8%, 15.2%, and 7.0%), and hypothyroidism (4.5%, 21.2%, and 2.3%).

The investigators of IMpower150 lead by Marin Reck, MD of Lugen Clinic, conclude from this sub-analysis that ABCP may be a novel treatment option for patients with 

-mutant NSCLC who failed treatment with a TKI.

Reck M, Mok T, Socinski M, et al. IMpower150: Updated efficacy analysis in patients with EGFR mutations. Presented at: 2020 European Society of Medical Oncology Virtual Congress. September 19-21, 2020; Virtual. Abstract 1293P.

Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

. 2018; 378(24):2288-230. doi: 10.1056/NEJMoa171694

Atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel demonstrated continued progression-free survival and overall survival benefit at 20 months of follow-up compared with chemotherapy alone in patients with chemotherapy-naïve metastatic nonsquamous non–small cell lung cancer who harbor an EGFR mutation, IMpower150 study results show.

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