Case Review of a 71-Year-Old Woman Presenting With DLBCL

Assessing Risk to Guide First-Line Treatment Selection in DLBCL

Second-Line Therapy Options in DLBCL

The L-MIND Trial in R/R DLBCL

Later Lines and Future Directions in DLBCL

A 71-year-old woman presented with fatigue, weight loss and pruritus

PE: palpable axillary and femoral lymphadenopathy; palpable spleen 3 cm below the midclavicular line

Labs: Hb 9.8 g/dL, LDH 2x ULN; renal and hepatic function WNL

Excisional biopsy of a right enlarged axillary lymph node confirmed DLBCL, GCB subtype

FISH panel: t(14;18) translocation with BCL2 rearrangement, no MYC or BCL2 rearrangements

Whole body PET/CT scan showed FDG avidity in the bilateral axillary and femoral regions, largest lymph node 3.6 cm in right axillary space; splenomegaly

Bone marrow biopsy showed involvement of DLBCL in the bone marrow

First post-treatment PET/CT scan unremarkable; metabolic CR based on Deauville criteria

9 months later there was relapse of disease with new cervical and mediastinal lymphadenopathy

Core needle biopsy of a cervical lymph node confirms a relapse of DLBCL, GCB subtype

Videos

Matthew Lunning, DO, presents a case study of a 71-year-old woman with relapsed/refractory diffuse large B-cell lymphoma. 

A 71-Year-Old Woman with Relapsed/Refractory DLBCL

Case Overview: 68-Year-Old Woman with ALK+ NSCLC

Treatment Options in ALK+ NSCLC

FDA Approval of Frontline Brigatinib in ALK+ mNSCLC

ALTA-1L Trial: Brigatinib

Sequencing ALK Inhibitors

ALK+ mNSCLC: Advancements Made and What’s Next

Case: A 68-Year-Old Woman with ALK+ Non–Small Cell Lung Cancer

A 68-year-old woman presented with fatigue, wheezing and decreased appetite

PE: wheezing on auscultation; ECOS PS 1
 

Chest x-ray showed a left lower lobe mass

Chest/abdomen/pelvic CT scan confirmed a 6.8-cm left lower lobe lung mass and a suspicious liver lesion

PET scan showed activity in the left lower lobe mass and liver

MRI of the brain showed several subcentimeter lesions without edema

Bronchoscopy with transbronchial biopsy of the left lower lobe mass confirmed lung adenocarcinoma

Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay

Karen Reckamp, MD, comments on the management and treatment of a 68-year-old woman with ALK+ NSCLC, as well as data demonstrated in the ALTA-1L trial, use of brigatinib, and her own clinical experiences.

A 68-Year-Old Woman with ALK+ Non–Small Cell Lung Cancer

A 57-year-old man presented with fatigue, anorexia, and occasional rib pain

PE: mild right-sided chest tenderness on palpation 


Chest x-ray showed multiple right upper lobe masses

Chest/abdomen/pelvic CT scan confirmed 3 masses (largest 6.5 cm)

PET scan showed activity in the right upper lobe masses

MRI of the brain showed multiple scattered lesions, consistent with multifocal brain

Bronchoscopy with transbronchial biopsy of the right upper lobe mass confirmed lung adenocarcinoma, invasive mediastinal

ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET

Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay

Managing patients with who progress on a TKI,  the role of re-biopsy at progression of disease, and the future treatment landscape for ALK+ mNSCLC. 

ALTA-1L Trial in ALK+ mNSCLC 

Approaching TKI (tyrosine kinase inhibitor)-based therapy for the first-line management of ALK+ mNSCLC. 

First-line Treatment Options for ALK+ mNSCLC 

Joshua M. Bauml, MD, presents the case of a 57-year-old man with ALK fusion+ non-small-cell lung cancer (NSCLC) and discusses recommended molecular tests to identify patients with molecular driver alterations. 

Case Overview: 57-Year-Old Man With ALK+ NSCLC 

Joshua M. Bauml, MD, provides insight on the treatment of ALK fusion+ non-small cell lung cancer with tyrosine kinase inhibitors. 

Case-Based Peer Perspectives: 57-Year-Old Man With ALK+ Non–Small Cell Lung Cancer

Sara A. Hurvitz, MD, director of the Breast Cancer Clinical Research Program and co-director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, discusses sequencing the current therapies for patients with HER2-positive breast cancer.

Hurvitz says sequencing is tricky because there are not a lot of data to inform that type of decision. Taxane-based therapy with the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) is used in the first-line setting based on the findings from the CLEOPATRA study (NCT00567190). This will be the frontline standard until a new agent goes head-to-head against this combination.

The second-line standard is trastuzumab emtansine [T-DM1; Kadcyla] based on the EMILIA (NCT00829166) and TH3RESA trials (NCT01419197). The combination of tucatinib (Tukysa), capecitabine, and trastuzumab is also available for use in the second-line setting, but it wasn’t compared directly with T-DM1 in the HER2CLIMB trial (NCT02614794). Hurvitz says she would reserve the use of that regimen for patients who have central nervous system metastases.

There are many regimens available in the third-line setting, and the sequencing of these options hasn’t been tested in a randomized clinical trial yet. Right now, sequencing is based on tolerability, the toxicity profile, and the data relating to the agents. Many physicians would use trastuzumab deruxtecan as our third-line agent of choice, but that may be moving up into earlier-line settings as new data accumulate from the phase 3 trials that are ongoing, according to Hurvitz.

Sara A. Hurvitz, MD, discusses sequencing the current therapies for patients with HER2-positive breast cancer.

Sequencing Newer Agents in HER2-Positive Breast Cancer

I think the future of treatment for ovarian cancer is really exciting. For a long time, the treatment options available to us were pretty stagnant. The PARP inhibitor explosion has offered so much hope for us as physicians and for our patients. We are extending progression-free survival, and we think we may even be curing some patients who were placed on it in the frontline setting, especially patients in the SOLO-1 study. Future studies will look at how we can exploit these PARP inhibitors even more. How can we overcome PARP resistance? We need to see how combining them with other treatments, for example, in the PAOLA trial with bevacizumab, to see how we can extend progression-free survival. Immunotherapy in ovarian cancer, especially with PD-1 and PD-L1 inhibitors, has quite frankly been a little disappointing.

We have not seen some of the same responses that have been seen in the melanoma realm or for our patients with endometrial cancer. For a subset of patients with MSI [microsatellite instability]-high tumors or high tumor mutational burden, immunotherapy can offer them a benefit. Of course, there are also trials out there looking at how to combine immunotherapy with other drugs to treat ovarian cancer and make treatment more effective. In some of the ovarian cancer vaccine trials, which provide a different way of looking at immunotherapy,

at least the preliminary results have been very exciting. I am looking forward to more clinical trials coming out addressing that. In regard to unmet needs, we need better screening for these patients. It is terrible that we are diagnosing the majority of these patients at stage III or IV of their disease. 

Even though we are helping our patients live longer, it is still very hard to cure their disease. That speaks to the fact that we need a better way to find these diseases at an early stage when they are curable. When we treat patients with HRD [homologous recombination deficiency]-negative cancers or with platinum-resistant cancers, we know that those cancers are much more difficult to treat; at that point, patients have a worse prognosis. It is difficult to find therapeutics that help those patients. Things like antibody-drug conjugates or other targeted therapies hold a lot of promise, and trials are ongoing.

Case: A 63-Year-Old Woman With Recurrent Ovarian Cancer

A 63-year-old female presented with early satiety and abdominal discomfort

PMH: unremarkable, postmenopausal; no known family history of cancer

PE: left lower quadrant tenderness on palpation

Pelvic exam with transvaginal ultrasound showed a left ovarian mass

Transvaginal U/S showed a left ovarian mass

Chest/abdomen/pelvis CT with contrast confirmed a left adnexal 4.4-cm mass with paraaortic lymph node involvement and ascites

Paracentesis (1000 cc) cytology confirmed high-grade epithelial ovarian cancer

Diagnosis: Stage III, high-grade epithelial ovarian cancer

Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0

Paclitaxel/carboplatin q3 weeks for 6 cycles; CA-125 decreased; PR

At 7-month post treatment follow-up imaging showed progression of disease

Paclitaxel/carboplatin + bevacizumab was initiated q3 weeks for 6 cycles

An expert in ovarian cancer considers the future of ovarian cancer treatment, the use of PARP inhibitors and overcoming PARP resistance, and the emerging treatments options.

Looking to the Future of Ovarian Cancer Treatment

For this patient, niraparib was definitely the right choice. Had we known about the results of the PRIMA or PAOLA trials when she was initially treated, we probably would have put her on it in the first-line maintenance setting. We know, at that point especially, that we can extend progression-free survival significantly for this patient population. It has also been FDA approved for use in the recurrent setting. It was definitely the right choice for this patient. We often have long discussions among ourselves and with the patients about how long to continue PARP inhibitors. Some studies continue them for up to 2 years. Niraparib has been continued for up to 3 years. I think, at that point, if patients are without evidence of disease, it is reasonable to discontinue that course of treatment, but some patients get it very nervous about discontinuing it. 

It is important to talk to our patients about the fact that we do not really have any long-term safety data beyond the 3-year mark. If we decide to continue as a physician and patient together, then the patient needs to accept that there may be risks that we are unaware of, such as myelodysplastic syndrome, and they need to be monitored over time. I think, as more of these studies come out and time goes on, we will have a better idea of how long to keep patients on treatment. One of the other questions that has come up relates to the fact that the trials that were first released were in the recurrent setting; we were putting everyone with platinum-sensitive disease on PARP inhibitors.

Now, we have all these data from the SOLO-1 and the PRIMA trials, both of which concluded that it was very effective in the upfront setting. So if a patient has had a PARP inhibitor in the upfront setting, and it was successful, and they still have platinum-sensitive disease, do you rechallenge? Do you rechallenge after that patient has had a response to a platinum-based regimen in the recurrent setting? The answer, of course, is that we do not know. There are trials ongoing that are looking at that right now. I think it has to be taken on a case-by-case basis.

Erin Crane, MD, discusses the role of PARP inhibitors in the treatment of ovarian cancer.

Use of PARP Inhibitors in Recurrent Ovarian Cancer 

 The phase 3 NOVA trial was a randomized, double-blinded placebo-controlled trial. It was in the setting of recurrent epithelial ovarian cancer, in patients who had either a partial or complete response to a platinum-containing regimen. Patients were randomized in a 2:1 fashion to niraparib 300 mg daily after completion of chemotherapy versus the placebo. There were 2 cohorts, and they were subdivided into patients with BRCA mutations and patients without BRCA mutations. The patients without BRCA mutations were further subdivided into 2 groups: patients who were homologous recombination proficient and patients who were homologous recombination deficient [HRD]. The primary end point for the study was progression-free survival.

In regard to the HRD-negative cohort, we know those patients can be harder to treat, and HRD negativity can essentially serve as a surrogate for platinum resistance. Those patients did not experience as much of a benefit, but still they had a 7-month progression-free survival improvement versus 4 months in the placebo group. 

I think it is something to take into consideration for patients in the recurrent setting; a 3-month progression-free survival benefit may be more clinically meaningful for that subset of patients. That is 3 more months that they are off cytotoxic treatment. This led to the FDA approval of niraparib in the particular setting of treating patients with recurrent epithelial ovarian cancer who had had a complete or partial response to prior platinum-containing compounds. This was agnostic of BRCA or HRD status.

The long-term safety outcomes are pretty similar across the board for PARP inhibitors. When you look at the NOVA phase 3 trial, about 25% of patients experienced grade 3 or 4 thrombocytopenia. About 20% of the patients had neutropenia; about 25% had anemia. Most of these issues can be mitigated by dose reductions. Actual discontinuation related to thrombocytopenia, for example, only occurred 3% of the time. In clinical practice, it is pretty easy to mitigate these [adverse] effects. If someone comes in and has grade 3 or 4 toxicity, generally, we hold the niraparib until that toxicity is resolved; for example, for patients with thrombocytopenia, we will wait until the platelet count has resolved to over 100,000 per μL. Once it has resolved, you drop the dose by 100 mg.

In the trial, that was pretty consistent. About one-third of patients did require a dose reduction. We know, from the trial—we say things like weights and plates. For patients who are less than 75 kg, or who have a platelet count that is less than 150,000 per μL starting out of the gate, we know those patients are more likely to require a dose reduction. Other nonhematologic [adverse] effects like nausea are quite common. That was experienced by up to 75% of patients. However, again, this is a heavily pretreated population, and up to 35% of patients in the placebo group also experienced nausea. We know from clinical practice that if patients can stick with a regimen and get through the first 2 weeks with antiemetics, then in general the nausea does get better over time. Of course, fatigue can be an issue for patients. I think it is really important to allow patients to fully recover before starting them on a PARP inhibitor. 

Sometimes, during the first month after they finish chemotherapy, patients’ energy levels are not quite back to normal. It is important to give patients a bit of a break if they need it because there are [adverse] effects associated with PARP inhibitors and niraparib. More serious [adverse] effects like myelodysplastic syndrome, which can be fatal, are fairly uncommon. It occurs in 1% or less of the population, but it does require us to continue to monitor our patients’ laboratory test results, at least on a monthly basis, for the first year of treatment.

There was a specific separate publication that came out that looked at patient-reported outcomes, or PROs, which have become a really important part of clinical trials. Of course, we put patients on these experimental drugs that have [adverse] effects, but they also have to be tolerable. Fortunately, the patient-reported outcomes were similar, the quality-of-life scores were similar between the placebo and the niraparib group. It was a regimen that, overall, was well tolerated.\

Erin Crane, MD, provides an overview of the Phase 3 NOVA trial.