Glofitamab-gxbm (Columvi – Genentech), a bispecific CD20-directed CD3 T-cell engager, has received accelerated approval from the FDA for IV treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, or large B-cell lymphoma (LBCL) arising from follicular lymphoma after ≥2 lines of systemic therapy. Accelerated approval was based on response rates and durability of response. Glofitamab is the second T-cell-engaging bispecific antibody to be approved in the US for treatment of DLBCL; epcoritamab-bysp (Epkinly), which is given subcutaneously, was approved earlier. Unlike epcoritamab, glofitamab is not approved for treatment of high-grade B-cell lymphoma.

Tafasitamab-cxix (Monjuvi – Morphosys), a CD19-directed cytolytic antibody, has received accelerated approval from the FDA for use in combination with lenalidomide (Revlimid) for treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from low grade lymphoma, in adults who are not eligible for autologous stem cell transplant. Accelerated approval was based on overall response rates.

The FDA has approved lisocabtagene maraleucel (Breyanzi – BMS) for treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, or follicular lymphoma grade 3B who have disease refractory to first-line chemoimmunotherapy, relapsed within 12 months of or after first-line chemoimmunotherapy, are not eligible for hematopoietic stem cell transplantation due to comorbidities or age, or have relapsed or refractory disease after ≥2 lines of systemic therapy. Breyanzi is an individualized cellular product prepared from the patient's own T cells, which are genetically modified to express chimeric antigen receptors (CAR) and then infused back into the patient. The CAR T-cell products axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) are also FDA-approved for treatment of large B-cell lymphoma.

Epcoritamab-bysp (Epkinly – Genmab), a bispecific CD20-directed CD3 T-cell engager, has received accelerated approval from the FDA for subcutaneous treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. Epcoritamab is the second T-cell-engaging bispecific antibody to become available in the US for treatment of non-Hodgkin's lymphoma; mosunetuzumab-axgb (Lunsumio) was recently approved for relapsed or refractory follicular lymphoma, a common subtype of non-Hodgkin's lymphoma.

Polatuzumab vedotin-piiq (Polivy – Genentech), a CD79b-directed antibody and microtubule inhibitor conjugate, has been approved by the FDA for use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for first-line treatment of diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or high-grade B-cell lymphoma (HGBL) in adults who have an International Prognostic Index (IPI) score ≥2. The drug was previously approved for use in combination with bendamustine and rituximab for treatment of patients with relapsed or refactory DLBCL, NOS, who received at least 2 prior therapies.

The FDA has approved cemiplimab-rwlc (Libtayo – Regeneron), an immune checkpoint inhibitor, for use in combination with platinum-based chemotherapy for first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults with no epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS1 aberrations and who are not candidates for surgical resection or chemoradiation. The drug was previously approved for first-line treatment of NSCLC in patients whose tumors have high PD-L1 expression and no genomic tumor aberrations. Cemiplimab is also approved for treatment of metastatic or locally advanced squamous cell carcinoma and locally advanced or metastatic basal cell carcinoma.

Mosunetuzumab-axgb (Lunsumio – Genentech), a bispecific CD20-directed CD3 T-cell engager, has received accelerated approval from the FDA for treatment of relapsed or refractory follicular lymphoma in adults who received ≥2 lines of systemic therapy. It is the first T-cell-engaging bispecific antibody to be approved in the US for this indication.

The Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa), which was previously approved by the FDA for treatment of mantle cell lymphoma, Waldenström's macroglobulinemia, and relapsed or refractory marginal zone lymphoma, has now been approved for treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults. The BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) were approved earlier for treatment of CLL and SLL.

The Bruton's tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca – Lilly) has received accelerated approval from the FDA for treatment of relapsed or refractory mantle cell lymphoma (MCL) in adults who received ≥2 prior lines of systemic therapy, including a BTK inhibitor. Accelerated approval was based on the response rate. The BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) are also approved for treatment of MCL.

The FDA has approved the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence – AstraZeneca) for oral treatment of relapsed or refractory mantle cell lymphoma. Acalabrutinib is the second BTK inhibitor to be approved for this indication; ibrutinib (Imbruvica) was approved in 2013.

Ibrutinib inhibits other kinases in addition to BTK and has been associated with severe adverse effects, particularly atrial fibrillation, infection, rash, and bleeding, that may be related to inhibition of kinases other than BTK.1 Acalabrutinib is a more selective BTK inhibitor than ibrutinib; whether this improved selectivity results in fewer adverse events is unclear.2

FDA approval of acalabrutinib was based on the results of a single-arm trial in 124 patients who had received a median of 2 previous therapies for mantle cell lymphoma. After a median follow-up of 15.2 months, 81% of patients treated with acalabrutinib 100 mg twice daily achieved an overall response and 40% achieved a complete response. The Kaplan-Meier estimated median overall survival rate at 12 months was 87%.3

The most common severe adverse events in the pivotal trial were neutropenia (10%), anemia (9%), and pneumonia (5%). There were no cases of atrial fibrillation and one case of severe hemorrhage. No head-to-head trials comparing acalabrutinib with ibrutinib are available to date.

The cost of 30 days' treatment with Calquence (100 mg bid) is $14,064 and with Imbruvica (560 mg once daily) is $12,180.4

1. AP Bye et al. Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Adv 2017; 1:2610.
2. J Wu et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol 2016; 9:21.
3. M Wang et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet 2018; 391:659.
4. Approximate WAC. WAC = wholesale acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. October 5, 2018. Reprinted with permission by First Databank, Inc. All rights reserved. ©2018. www.fdbhealth.com/policies/drug-pricing-policy.

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The FDA has approved the anti-CD30 antibody-drug conjugate brentuximab vedotin (Adcetris – Seattle Genetics) for use in combination with chemotherapy for IV treatment of adults with previously untreated stage 3 or 4 classical Hodgkin's lymphoma (cHL). Adcetris was approved earlier for consolidation treatment of cHL and for treatment of relapsed or refractory cHL, anaplastic large cell lymphoma, and CD30-expressing mycosis fungoides.

FDA approval for the new indication was based on the results of an open-label trial (ECHELON-1) in 1334 patients with previously untreated stage 3 or 4 cHL.1 Patients were randomized to receive a regimen consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; standard initial treatment for cHL) or a regimen that included brentuximab vedotin instead of bleomycin (A+AVD). Bleomycin can cause severe pulmonary toxicity and is often dropped from the regimen after several cycles of ABVD.

The 2-year modified progression-free survival rate (the primary endpoint; defined as time to progression, death, or noncomplete response and use of subsequent anticancer therapy) was 82.1% with A+AVD and 77.2% with ABVD, a statistically significant difference.

Neutropenia and peripheral neuropathy were more common with A+AVD than with ABVD (58% vs 45% and 67% vs 43%, respectively). Severe pulmonary toxicity was more common with ABVD (3% vs <1%). Of the 9 deaths that occurred in the A+AVD group, 7 were related to neutropenia; 11 of the 13 deaths in the ABVD group were related to pulmonary toxicity. PET scans to evaluate the response to therapy, which could have permitted discontinuation of bleomycin after the first 2 cycles and decreased the risk of pulmonary toxicity, were not performed.2

Six cycles of A+AVD have been estimated to cost up to $850,000, compared to less than $8000 for ABVD.3 There is no evidence to date that the new regimen improves overall survival in patients with previously untreated stage 3 or 4 cHL.

1. JM Connors et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 2018; 378:331.
2. T Hilal. Brentuximab vedotin for stage III or IV Hodgkin's lymphoma. N Engl J Med 2018; 378:1558.
3. JP Greer. Brentuximab vedotin for stage III or IV Hodgkin's lymphoma. N Eng J Med 2018; 378:1559.

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The FDA has approved axicabtagene ciloleucel (Yescarta – Kite) for treatment of adults with relapsed or refractory CD19+ large B-cell lymphoma after ≥2 lines of systemic therapy. Yescarta is an individualized cellular product prepared from the patient's own T cells, which are genetically modified to express chimeric antigen receptors (CAR) and then infused back into the patient. It is the second CAR T-cell immunotherapy to become available in the US. Tisagenlecleucel (Kymriah), a CAR T-cell product previously approved for treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in patients ≤25 years old, was recently also approved for relapsed or refractory CD19+ large B-cell lymphoma after ≥2 lines of systemic therapy.

The FDA has granted accelerated approval to copanlisib (Aliqopa – Bayer), an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, for treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies. Follicular lymphoma is a common subtype of non-Hodgkin's lymphoma. Copanlisib is the second PI3K inhibitor to be approved for this indication; idelalisib (Zydelig), which is administered orally twice daily, was the first.

The FDA has approved tisagenlecleucel (Kymriah — Novartis), an individualized, genetically-modified cellular product, for treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in patients ≤25 years old. The patient's own T cells are genetically modified to express chimeric antigen receptors (CAR) and then reinfused. Kymriah is the first CAR T-cell immunotherapy to become available in the US. A CAR T-cell product for B-cell non-Hodgkin's lymphoma is expected to be approved soon.

The FDA has approved a 0.016% gel formulation of the nitrogen mustard mechlorethamine (Valchlor – Actelion) for second-line topical treatment of patients with stage IA or IB mycosis fungoides, the most common type of cutaneous T-cell lymphoma. Topical nitrogen mustard has been used off-label for decades for this indication, usually as a pharmacy-compounded ointment, but no clinical trials evaluating its efficacy and safety have been done. Mechlorethamine is also available in an injectable formulation (Mustargen – Recordati) for the same and other indications.

FDA approval of Valchlor was based on a randomized, non-inferiority trial in 260 patients with stage IA, IB, or IIA mycosis fungoides comparing it to a 0.02% mechlorethamine compounded ointment, both applied once daily for up to 1 year. Response rates, based on a composite assessment of index lesion severity, were slightly higher with the gel (59% vs. 48%, which met prespecified criteria for noninferiority). Based on a Kaplan-Meier analysis, the estimated time to a 50% response rate was shorter with the gel than with the compounded ointment (26 weeks vs. 42 weeks). It was also estimated that at least 90% of the responses in both treatment arms would be maintained for ≥10 months, the maximum follow-up period in the trial.

No serious drug-related adverse effects were observed, and no systemic absorption of the drug was detected. About 20% of patients treated with the gel and about 17% of those treated with the ointment withdrew from the study because of skin irritation, which has always been the most troublesome side effect of topical mechlorethamine.1

A thin layer of mechlorethamine gel should be applied to each affected area of the skin once daily. The drug should be stopped if skin ulceration, blistering, or moderately severe or severe dermatitis occurs. Treatment can be restarted at a frequency of once every 3 days for 1 week and, if tolerated, can be increased to every other day for another week, and then to once daily. The gel should be stored in the refrigerator and applied within 30 minutes of removing it from the refrigerator. The cost of a 60-g tube is $2900.2

1. SR Lessin et al. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 2013; 149:25.
2. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. April 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.

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The FDA has approved belinostat (Beleodaq – Spectrum), an IV histone deacetylase (HDAC) inhibitor, for treatment of adults with relapsed or refractory peripheral T-cell lymphoma (PTCL). It is the third IV drug approved by the FDA for PTCL. The first was the antifolate drug pralatrexate (Folotyn), which was followed by the HDAC inhibitor romidepsin (Istodax). Vorinostat (Zolinza), an oral HDAC inhibitor, is FDA-approved for treatment of cutaneous T-cell lymphoma.

Nelarabine (Arranon - GlaxoSmithKline), a prodrug of the deoxyguanosine analog 9-β-D-arabinofuranosylguanine (ara-G), has been approved by the FDA for treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to, or has relapsed following, treatment with at least two chemotherapy regimens.

Bexxar, a combination of the monoclonal antibody tositumomab and radiolabeled Iodine-131 tositumomab (Corixa Corp/GlaxoSmithKline) has been approved by the FDA for a single treatment of relapsed follicular non-Hodgkin's lymphoma (NHL) in patients who are refractory to rituximab (Rituxan - Medical Letter 1998; 40:65). It is the second radioimmunoconjugate to be approved for refractory NHL; yttrium-90 linked to ibritumomab tiuxetan (Zevalin) was approved in 2002. Tositumomab, like ibritumomab, is a monoclonal antibody of mouse origin that binds to the CD20 antigen present on the surface of >90% of malignant B cells.

The tables in this article list drugs used for treatment of cancer in the USA and Canada and their major adverse effects. The choice of drugs in Table I is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. In some cases, such as elderly patients or those with many co-morbid illnesses, the regimen of choice might not be suitable. For many of the cancers listed, surgery and/or radiation therapy may be the treatment of choice or may also be part of the management. Anticancer drugs and their adverse effects are listed in Table II on page 46. A partial list of brand names appears on page 52.

The tables in this article list drugs used for treatment of cancer in the USA and Canada. The choices of drugs in Table 1 is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. For many of the cancers listed, surgery and/or radiation therapy are also part of the management of the disease.