Follicular and indolent NHL

Since regulatory approval by the US FDA in 1997 for the treatment of patients with recurrent or refractory follicular or indolent NHL, indications have been extended to provide 8 rather than 4 weekly courses and to retreat patients who had responded previously.¹⁸ After relapse, retreatment with a similar course of rituximab produced an overall response rate of 38% in 60 patients, with 10% complete remissions. Median time to progression exceeded 15 months.¹⁹ Combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (R-CHOP) in 40 patients with low-grade follicular lymphoma, some of whom had been treated previously, resulted in an overall response of 100%, with 58% complete remissions and 42% partial remissions. Median time to progression exceeded 40.5 months.²⁰ In a meta-analysis of 7 trials with 1943 patients with follicular lymphoma, other indolent lymphomas, and the more aggressive mantle cell lymphoma, the addition of rituximab to chemotherapy improved overall survival (OS), although the statistical significance was higher with indolent lymphomas than with the mantle cell histotype.²¹ The addition of rituximab to cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy prolonged time to progression in patients with newly diagnosed follicular NHL, resulting in FDA approval in 2006 for use of rituximab in first-line therapy.²² Maintenance therapy with rituximab has prolonged progression-free survival (PFS) in four randomized trials, while OS has been extended in some but not all studies.²³ In 2011, the US FDA approved rituximab for maintenance therapy based on a randomized comparison of rituximab (up to 12 8-week cycles) to no maintenance therapy in 1018 patients with high tumor burden follicular NHL who had complete or partial response to rituximab plus one of three chemotherapy regimens. Maintenance rituximab reduced the risk of a PFS event by 46% (P < 0.0001). At 3 years, PFS in the rituximab maintenance group was 74.9% versus 57.6% in the observation group (P < 0.0001).²⁴

Diffuse large B-cell NHL

More aggressive diffuse large B-cell lymphoma (DLBCL) has been less responsive to rituximab alone. Among 54 patients with disease in relapse, the overall response rate to 8 cycles of rituximab was 31%, including 9% complete remissions with a median time to progression in responders of 8 or more months.²⁵ Subsequently, 399 elderly patients with more aggressive DLBCL were randomized to receive R-CHOP or CHOP alone. A complete response rate of 76% was observed with the combination, compared with 60% with CHOP alone.²⁶ Event-free survival (P < 0.005) and OS (P < 0.01) were prolonged significantly by the addition of rituximab. Similar results were obtained in two confirmatory trials,^{27, 28} both in young and elderly individuals, resulting in FDA approval in 2006 for use of R-CHOP in DLBCL, and providing the first improvement in the systemic treatment of DLBCL in two decades. In a recent meta-analysis of 7 trials involving 1470 patients with relapsed or refractory DLBCL, maintenance therapy with rituximab provided numerically improved PFS and OS, but the differences were not statistically significant, whereas incorporation of rituximab in salvage therapy led to statistically significantly better OS (P = 0.02) and PFS (P < 0.05) than rituximab-free regimens.²⁹ However, the rate of infection-related adverse events was higher with rituximab treatment (RR = 1.37; P = 0.001).

CLL and Waldenstrom macroglobulinemia

Treatment with rituximab, alone or in combination with fludarabine, has been extended to CLL.³⁰ In early studies, only a very modest response rate (15%) was observed with low standard doses of rituximab, possibly related to the lower concentration of CD20 on the CLL cell surface (8–15,000 vs 90,000 sites/cell) and to the shedding of soluble CD20, creating an “antigenic sink.”^{31, 32} Treatment with higher doses of rituximab or thrice weekly administration achieved an overall response rate of 46%, with an even higher response rate in previously untreated patients.³¹ A Cancer and Leukemia Group B (CALGB) trial of fludarabine and rituximab in 42 patients with CLL yielded a 100% response rate, with 48% of patients achieving complete remission.³³ On the basis of the two randomized phase III studies where the addition of rituximab to fludarabine and cyclophosphamide extended PFS by 10–19 months in previously treated and untreated patients with CLL,^{34, 35} the US FDA approved rituximab in combination with fludarabine and cyclophosphamide in 2010. Rituximab has also been used with alkylating agents to treat Waldenstrom macroglobulinemia. One study reported a 74% response rate and 67% 2-year PFS with a combination of rituximab, dexamethasone, and cyclophosphamide.³⁶

Autoimmune disease

Depletion of B lymphocytes has contributed to the management of autoimmune diseases. Rituximab has been approved in combination with methotrexate for the treatment of rheumatoid arthritis that has failed anti-tumor necrosis factor (TNF) therapy, as well as for treatment of granulomatosis polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis (MPA) with glucocorticoids.³⁷

Toxicity

Rituximab therapy is generally well tolerated. Most side effects are infusion related and occur within the first few hours of treatment. Adverse events generally last minutes to hours and include chills, fever, nausea, vomiting, fatigue, headache, pruritus, and the sensation of throat swelling.³⁸ Although side effects are experienced by up to 77% of patients, they are severe in only 10%.³⁹ Normal B-lymphocyte counts can decrease to zero after initial infusion; recovery begins by 6 months and is generally complete by 9–12 months. As CD20 is not expressed on mature plasma cells, immunoglobulin levels are maintained, and intercurrent infections requiring hospitalization occurred in only 2% of patients during 1-year follow-up. Following FDA approval in 1997 and before 2002, >125,000 patients were treated with rituximab in the United States. Among these individuals, only eight deaths were associated with treatment related to the development of infusion reactions, paraneoplastic pemphigus, Stevens-Johnson syndrome, and toxic epidermal necrolysis.⁴⁰ More than 120 cases of interstitial lung disease have been reported, generally when rituximab has been given with chemotherapy, but associated with monotherapy in 25%.⁴¹ In recent years, rituximab treatment has been linked to reactivation of hepatitis B virus (HBV) in HBsAg-negative/HBcAb-positive patients. In one meta-analysis of 578 patients across 15 studies, the risk of reactivation was estimated at 6.3%,⁴² suggesting that patients should be tested and antiviral prophylaxis given to patients with evidence of previous HBV infection who are receiving rituximab.

Mechanism of action and resistance

The mechanism(s) by which rituximab kills leukemia and lymphoma cells is not completely understood but probably involves ADCC, CDC, and the direct effect of CD20 ligation.⁴³ In cancer cells, cross-linking CD20 can induce cell cycle arrest, inhibit DNA synthesis, activate caspases, and induce apoptosis.³³ Sensitization to chemotherapy may relate to inhibiting the constitutive activation of AKT, thus downregulating the antiapoptotic protein Bcl-XL.⁴⁴ NK cells, macrophages, and polymorphonuclear leukocytes can be important effectors for ADCC,³³ and a correlation has been observed in some studies, between clinical response to rituximab and the presence of specific allelic polymorphisms in the FcγRIIIa and FcγRIIa receptors for IgG that are required to mediate ADCC.⁴⁵ Individual NK cells are capable of “serial killing” of multiple lymphoma cells, particularly in the presence of rituximab that creates a “cap” at one pole of the cancer cell containing CD20, ICAM-1, and the microtubule-organizing center that enhances sensitivity to NK killing.^{3, 46} The response to rituximab is impaired in mice genetically deficient in C1q that lack the first component of the CDC pathway but that have intact ADCC.⁴⁷ Clinical resistance to rituximab treatment rarely involves loss of CD20 expression but can be associated with upregulation of complement resistance proteins CD55 and CD59.⁴⁸ Interestingly, different patterns of gene expression have been observed in lymphoma cells obtained before treatment from responders and nonresponders to rituximab.⁴⁹ Gene expression in tumors that failed to respond resembled that in normal lymphoid tissues and exhibited higher expression of genes encoding certain complement components and genes involved in cytokine, T cell, and TNF signaling.

Toxicity

The most common (>5%) adverse reactions with ofatumumab in combination with chlorambucil were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Overall, 67% of patients who received ofatumumab experienced one or more episodes of infusion reaction and 10% experienced a grade 3 or greater infusion reaction.

Toxicity

The most common side effects in participants receiving obinutuzumab in combination with chlorambucil were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and fever. Obinutuzumab was approved with a boxed warning regarding HBV reactivation observed with other anti-CD20 antibodies and rare cases of progressive multifocal leukoencephalopathy identified in participants on other trials of obinutuzumab.

Chlorambucil in combination with either obinutuzumab or ofatumumab provides an alternative for elderly CLL patients with comorbidities who are unlikely to tolerate fludarabine-based therapy.¹⁰

Toxicity

Common adverse reactions (>10% compared to placebo) during treatment with siltuximab include pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections. Consequently, siltuximab provides an excellent example of a targeted therapy against a cytokine that drives a rare, but debilitating lymphoproliferative disease.

Colorectal cancer

Weekly treatment with cetuximab alone produced partial remissions in 9% of 57 patients with chemotherapy-refractory colorectal cancer.⁶² In two larger trials, a combination of irinotecan and cetuximab was used to treat a total of 450 patients with documented metastases from EGFR-positive colorectal cancer who had received irinotecan previously.⁶³ A combination of cetuximab and irinotecan produced a partial response in 17–23% compared with 11% of patients retreated with irinotecan alone. In one study, PFS, but not OS, was prolonged significantly from 1.1 to 4.1 months with the combination. In a subsequent phase III study, 1289 patients with recurrent EGFR expressing colorectal cancer who had been treated previously with first-line fluorouracil- and oxaliplatin-containing regimens were randomized to cetuximab plus irinotecan or irinotecan alone. Cetuximab improved disease-free survival significantly, but not OS, possibly related to cross-over in 47% of patients.⁶⁴ Interestingly, the level of EGFR expression has not correlated with response to cetuximab-based therapy. Consistent with this observation, 4 of 16 previously treated patients (25%) with EGFR immunohistologically negative cancers responded to a combination of cetuximab and irinotecan.⁶⁰ Consequently, patients should not be excluded from treatment based on immunohistochemical evaluation of EGFR. In 2004, the US FDA provided accelerated approval for cetuximab in combination with irinotecan to treat patients with irinotecan-resistant colorectal cancer. In 2007, regular approval was given, based on a trial where 572 patients with advanced EGFR-positive colorectal cancers that had failed oxaliplatin- and irinotecan-based regimens were randomized to BSC with or without cetuximab until progression. Cetuximab improved OS from 4.6 to 6.1 months (P = 0.0048).⁶⁵ Approval was given also for use of cetuximab as a single agent to treat colorectal cancer that had failed oxaliplatin- and irinotecan-based regimens.

Similar to clinical results with small molecule inhibitors and other monoclonal antibodies reactive with EGFR, responses to cetuximab are rare in cancers with KRAS mutations.⁶⁶ In retrospect, exclusion of patients with KRAS mutations affected the outcome substantiallyof the CRYSTAL trial where 1217 previously untreated patients with metastatic colorectal cancer were randomized to FOLFIRI alone or in combination with cetuximab, irrespective of KRAS mutation status.^{67, 68} Addition of cetuximab prolonged median PFS from 8.1 to 8.9 months (P = 0.036) and did not affect OS. When cancers were tested for KRAS mutations, the addition of cetuximab to FOLFIRI increased OS (19.5–23.5 months), PFS (8.1–9.5 months), and ORR (39% vs 57%) in patients with KRAS wild-type tumors. In patients with K-RAS mutant cancers, no improvement in OS, PFS, or ORR was associated with the addition of cetuximab to FOLFIRI. Supportive data were found in two other randomized trials where only patients with KRAS wild-type cancers benefitted,^{69, 70} resulting in approval in 2012 for cetuximab in combination with FOLFIRI for previously untreated patients with colorectal cancer.

Head and neck cancer

Cetuximab has also been approved for use in squamous cell carcinoma of the head and neck (SCCHN). In a pivotal multinational, phase III study, 424 patients with locally advanced head and neck cancers were randomized to high-dose radiotherapy or to a combination of radiotherapy with cetuximab.⁷¹ The addition of cetuximab increased the duration of locoregional control from 15 to 24 months and increased OS from 29 to 49 months. When cetuximab was administered to patients with recurrent SCCHN who had progressed on platinum-based therapy, response rates of 10–13% were observed over three prospective trials (n = 103) with disease control rates of 46–56%.⁷² The median time to disease progression ranged between 2.2 and 2.8 months, and the median OS ranged between 5.2 and 6.1 months.

Cetuximab has also improved the efficacy of platinum-based chemotherapy for SCCHN. Approval by the US FDA in 2011 was based on a multicenter trial in 442 patients with locoregionally recurrent or metastatic head and neck cancer who were randomly assigned to receive cisplatin (or carboplatin) with 5-FU with or without cetuximab.⁷³ Significant improvements were seen in OS (10.1 months vs 7.4 months; P = 0.34), PFS (5.5 months vs 3.3 months; P < 0.0001), and objective response rates (35.6% vs 19.5%; P = 0.0001) in patients receiving cetuximab plus chemotherapy.

Toxicity

Side effects in a majority of patients included an acneiform rash, predominantly on the face and upper torso (Figure 1), and a composite syndrome of asthenia, fatigue, and malaise or lethargy. Treatment with minocycline can reduce the severity of the acneiform rash.⁷⁴ Meta-analysis has found that the intensity of the rash correlates with OS, PFS, and ORR.⁷⁵ Hypomagnesemia results from the direct effect of cetuximab on EGFR in distal renal tubules, producing magnesium wasting.⁷⁶ A small minority of patients have experienced severe anaphylactic reactions, often on the initial infusion of cetuximab, related to a preexisting IgE antibody against galactose–α-1,3-galactose oligosaccharide found on the Fab portion of the cetuximab heavy chain.⁷⁷

Toxicity

A similar spectrum of side effects has been observed with panitumumab and cetuximab. Acneiform rash and hypomagnesemia have been most notable.⁸¹ To date, fewer allergic reactions have been observed with panitumumab than with cetuximab.

Breast cancer

In early clinical studies, trastuzumab produced objective regression of recurrent breast carcinoma in 12–15% of 269 heavily pretreated women.^{93, 94} Although cisplatin has demonstrated marginal activity against breast cancer in previous studies, a combination of cisplatin and trastuzumab produced an objective clinical response in 24% of 37 patients, with median duration of 8.4 months.⁹⁵ A critical international multi-institutional study was performed in 469 women with recurrent breast cancer.⁹⁶ Patients who had not previously received adjuvant therapy with doxorubicin were randomized to doxorubicin (or epirubicin) and cyclophosphamide, with or without trastuzumab. Women who had received adjuvant doxorubicin were randomized to paclitaxel with or without trastuzumab. The addition of trastuzumab to chemotherapy was associated with longer time to disease progression (median 7.4 months vs 4.6 months; P < 0.001), higher objective response rate (50% vs 32%; P < 0.001), longer duration of response (median 9.1 months vs 6.1 months; P < 0.001), and longer survival (median 25.1 months vs 20.3 months; P = 0.01). This study resulted in the approval of trastuzumab by the US FDA in 1998 and the EU in 2000 for the treatment of recurrent HER-2-overexpressing breast cancers. Subsequently, six large, multicenter adjuvant trials were undertaken (reviewed in Breast Cancer Neoplasms) to test whether the addition of trastuzumab improved the ability of chemotherapy to prevent recurrence of primary HER-2-positive breast cancer. Interim analysis in five of the six trials demonstrated sufficiently dramatic improvement in disease-free survival to terminate the clinical studies and to recommend use of trastuzumab in this setting.^97–99 Addition of trastuzumab produced a 46–58% reduction in risk of recurrence, associated with an absolute reduction of 8–12% at 3 years in the 5 positive trials. Similarly, mortality was reduced 33–59%, producing an absolute decrease of 2–6% at 3 years.

On the basis of the results of two of these trials (NSABP B31 and NCCTGN9831) including 3752 women, the FDA granted approval in 2006 for the addition of trastuzumab to cyclophosphamide, doxorubicin, and paclitaxel for adjuvant therapy of women with HER-2-overexpressed cancer.

Trastuzumab enhances the response rate to several other cytotoxic agents used to treat breast cancer, including vinorelbine, gemcitabine, and platinum compounds.^100–104 A randomized trial in 81 patients with metastatic HER-2-positive breast cancer who had not received chemotherapy for recurrent disease demonstrated a 51% response rate to vinorelbine and trastuzumab compared to a 40% response rate with paclitaxel and trastuzumab.¹⁰⁵ In most studies, only those breast cancers with strong expression of HER-2, driven by gene amplification, responded to the antibody alone or to a combination of antibody with chemotherapy. Immunohistochemistry can provide an initial screen for HER-2 overexpression, but 2+ to 3+ reactions should be confirmed with the more reliable fluorescence in situ hybridization assay.¹⁰⁶ HER-2 gene amplification can be acquired as breast cancers progress, arguing for repeated testing for HER-2 overexpression.¹⁰⁷ Because only a fraction of patients responds, overexpression of HER-2 is necessary, but not sufficient reason to ensure response to trastuzumab. Lack of response to trastuzumab correlated with lack of expression of the PTEN phosphatase, the enzyme that removes phosphate groups from PI3 and interrupts signaling through AKT.¹⁰⁸ Treatment with trastuzumab increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation through inhibition of Src that could no longer dock on the HER-2 receptor.

Gastric and GEJ cancers

In 2010, the FDA granted approval for trastuzumab in combination with cisplatin and a fluoropyrimidine (either capecitabine or 5-fluorouracil) for the treatment of patients with HER-2-overexpressing metastatic gastric or GEJ carcinomas who had not received prior treatment for metastatic disease. The approval was based on results of a single international multicenter open-label randomized clinical trial, BO18255 (ToGA trial), which enrolled 594 patients with locally advanced or metastatic HER2-overexpressing adenocarcinoma of the stomach or GEJ.¹⁰⁹ Patients were randomly assigned to receive trastuzumab plus chemotherapy or chemotherapy alone. The trial was closed after the second interim analysis, when the addition of trastuzumab was associated with improved median survival (13.5 months vs 11.0 months; P = 0.0038). An updated survival analysis demonstrated a persistent advantage to trastuzumab (13.1 vs 11.7) with the greatest benefit seen in HER-2 overexpressing cancers.

Toxicity

Treatment with trastuzumab is well tolerated and is associated with low-grade fever, chills, and fatigue that, generally, are observed with the first administration. In many studies, trastuzumab has been administered weekly, but it has been administered every 3 weeks at higher dosage with acceptable toxicity and trough levels.¹¹⁰ When trastuzumab has been combined with doxorubicin or paclitaxel, increased cardiotoxicity has been observed. In the pivotal trial that demonstrated the efficacy of trastuzumab in recurrent breast cancer, American Heart Association class III and IV cardiac dysfunction occurred in 27% of the group given trastuzumab with anthracycline and cyclophosphamide compared to 8% of the group given anthracycline and cyclophosphamide alone.¹¹¹ A similar degree of cardiac dysfunction was observed in 13% of patients who received paclitaxel and trastuzumab compared with 1% who received paclitaxel alone. Long-term treatment of 218 breast cancer patients with trastuzumab-based therapy for at least 1 year was associated with an 11% incidence of class III cardiac dysfunction.¹¹² In the six adjuvant trials where trastuzumab was given sequentially or concurrently with paclitaxel or carboplatin, but not doxorubicin, class III/IV cardiac dysfunction was observed in 0.5–4.1%.^{98, 99} Cardiac dysfunction generally responds to discontinuing trastuzumab and providing medical management. Thus, the benefits of trastuzumab for recurrent disease or adjuvant treatment generally outweigh the risks in patients with normal baseline cardiac function. The mechanism for trastuzumab-induced cardiac dysfunction remains obscure. Only low levels of HER-2 are found on cardiac myocytes, but trastuzumab can localize to the myocardium, and the ligand heregulin that binds to HER-2-HER-3 and HER-2-HER-4 dimers appears critical to the fetal development and survival of cardiac tissue under apoptotic stress.¹¹³ Use of less cardiotoxic anthracyclines in combination with trastuzumab offers one alternative. A neoadjuvant trial has been reported where concurrent epirubicin, paclitaxel, and trastuzumab produced a significantly higher pathological complete response (pCR) rate than did chemotherapy alone (67% vs 25%) without development of clinically evident congestive heart failure.¹¹⁴

Toxicity

The most common side effects reported in participants receiving pertuzumab plus trastuzumab and paclitaxel or docetaxel were hair loss, diarrhea, nausea, and neutropenia. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis. There is a black box warning for cardiac failure and fetal damage.

Toxicity

The most common (>25%) adverse drug reactions in the dinutuximab/RA group were pain, pyrexia, thrombocytopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common (>5%) serious adverse reactions in the dinutuximab/RA group were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

Colorectal cancer

In patients with previously untreated metastatic colorectal carcinoma, the addition of bevacizumab to irinotecan, fluorouracil, and leucovorin increased the overall response rate (34.8–44.8%) and significantly prolonged median PFS (7.4–10.4 months) and median OS (15.6–20.3 months).¹²⁸ This trial led to the initial FDA approval in 2004 of bevacizumab for use with chemotherapy for first-line therapy of colorectal cancer. Two subsequent randomized phase 2 trials have demonstrated improved response rate, PFS, and OS when bevacizumab was added to 5-FU and leucovorin.^129–131 In phase 3 studies where bevacizumab has been added to more effective first-line regimens, including FOLFOX-4 and XELOX, response rate, and OS were not significantly improved.^{132, 133} A number of combinations of bevacizumab and multiple drug combinations have provided similar results in noninferiority studies.¹³⁴ In second-line therapy, however, addition of a higher dose of bevacizumab to FOLFOX-4 significantly increased response rate (9–23%), PFS (4.7–7.3 months), and OS (10.8–12.9 months) in bevacizumab-naive patients, leading to the approval of bevacizumab for second-line therapy in 2006.¹³⁵ In patients with metastatic colorectal cancer who had progressed on bevacizumab in combination with irinotecan-based chemotherapy or oxyplatin-based regimens, continued use of bevacizumab in combination with the complementary chemotherapy regimen improved OS (11.2 months vs 9.8 months; P = 0.0062) and PFS (5.7 months vs 4.0 months; P < 0.0001), leading to approval for continued use of bevacizumab in second-line therapy.¹³⁶

Non-small-cell lung cancer

In previously untreated metastatic NSCLC, three phase III trials have studied the addition of bevacizumab to carboplatin/paclitaxel,^{137, 138} or to gemcitabine/cisplatin.¹³⁹ Significant increases have been observed in response rates (range 14–28.1%) with a more modest increase in PFS (0.6–2.7 months) or OS (0.5–2.0 months).¹³⁴

Breast cancer

Addition of bevacizumab to paclitaxel in first-line treatment of patients with recurrent metastatic breast cancer significantly increased response rate (21–37%) and PFS (5.9–11.8 months).¹⁴⁰ A modest, but significant, increase in PFS (8.0–8.8 months) was observed when bevacizumab was added to docetaxel.¹⁴¹ In second-line therapy, the addition of bevacizumab to capecitabine significantly increased the response rate (9–20%) but not PFS (4.2–4.9 months) or OS (14.5–15.1 months).¹⁴² Given the limited effect of bevacizumab in confirmatory trials, approval of the drug was withdrawn for breast cancer.

Renal cell cancers

A majority of sporadic RCCs exhibit inactivation of the von Hippel Lindau (VHL) gene with consequent overexpression of VEGF.¹⁴³ In a randomized phase 2 trial that compared two doses of bevacizumab (3 or 10 mg/kg every 2 weeks) with placebo in previously treated patients with RCC, a significant prolongation of PFS was observed when high-dose bevacizumab was compared with placebo (2.5–4.8 months, P < 0.01).¹⁴⁴ IFN-α is a standard initial therapy for RCC with a modest response rate and a survival advantage demonstrated in randomized trials. Two phase 3 trials have compared treatment with IFN-α and bevacizumab to IFN-α alone in previously untreated patients with RCC.^{145, 146} PFS was increased significantly from 5.2–5.4 to 8.5–10.2 months.

Glioblastoma multiforme (GBM)

Bevacizumab demonstrated activity against GBM (glioblastoma multiforme) in two single-armed trials, AVF3708g and NCI 06-C-0064E, where monotherapy produced a 20–25% response rate lasting a median of 3.9–4.2 months in a total of 141 patients who had relapsed after surgery, radiotherapy, and temozolomide.¹⁴⁷ This prompted accelerated FDA approval for use in this setting. A recent double-blind, randomized trial evaluated whether the addition of bevacizumab to radiotherapy and temozolomide would improve outcomes in 637 patients with newly diagnosed GBM.¹⁴⁸ Addition of bevacizumab increased PFS from 7.3 to 10.7 months (P = 0.007), but did not affect OS.

Ovarian cancer

In heavily pretreated patients with recurrent ovarian cancer, administration of bevacizumab, alone^{149, 150} or in combination with daily oral low-dose cyclophosphamide to provide “metronomic” therapy,¹⁵¹ has produced response rates of 16–24% with PFS of 4.4–7.2 months. Stabilization of disease for 6 months has been observed in approximately 40% of ovarian cancer patients. Four randomized studies have been performed evaluating the addition of bevacizumab to standard chemotherapy for front-line treatment (GOG 218¹⁵² and ICON7¹⁵³) and for recurrent “platinum sensitive” (OCEANS¹⁵⁴) and “platinum resistant” (AURELIA¹⁵⁵) disease.¹⁵⁶ PFS was improved in these studies by 3.8 months (P < 0.001), 1.7 months (P = 0.001), 3.3 months (P = 0.001), and 4.0 months (P < 0.0001), respectively. OS was not improved in any of the studies, but subsets of patients in GOG 218 and ICON7 with poor prognosis appeared to benefit. Lack of impact on OS overall and similar enhancement of PFS in first-line and recurrent disease has raised the question of whether treatment with bevacizumab should be delayed until disease recurrence.¹⁵⁶ Approval for use of bevacizumab in combination with chemotherapy for recurrent disease was granted based on the Aurelia trial.

Cervical cancer

Addition of bevacizumab to a combination of carboplatin with paclitaxel or topotecan increased OS by 3.7 months (from 13.3 to 17.0 months, P = 0.004) and increased the rate of response from 36% to 88% (P = 0.008) in a randomized trial including 452 women with recurrent, persistent, or metastatic cervical cancer.¹⁵⁷

Toxicity

In patients with NSCLC, RCC, colorectal, breast, cervical, and ovarian cancer, bevacizumab administration has been well tolerated by the majority. Grade 3 hypertension has been observed in approximately 20% of patients. While hypertension has been readily managed in most cases, malignant hypertension and fatal hemorrhagic stroke have been observed, arguing for aggressive monitoring and management of blood pressure. Significant proteinuria occurs in <5% of cases. Nasal bleeding has been observed. Greater risk for delayed wound healing and bleeding has been observed when bevacizumab was administered within 60 days of surgery.¹⁵⁸ In patients with NSCLC, major hemoptysis was associated with 4 deaths among 35 patients in one early trial. Life-threatening hemoptysis occurred most frequently in elderly males with squamous cell histology, tumor necrosis, and cavitation, as well as disease close to major vessels. Patients with these characteristics have been excluded from many trials. Thromboembolic events have been observed in 5–7.4% of participants on randomized trials in ovarian cancer.¹⁵⁶ Arterial thromboembolism has been observed in 2% of patients in large phase 3 trials across disease sites. In heavily pretreated patients with ovarian cancer, perforation of the bowel has been observed in 5–7% of cases, generally in the setting of partial small bowel obstruction and treatment response in lesions that involve the bowel wall. Bowel perforation has occurred in 2.6–3% of ovarian cancer patients on front-line adjuvant trials¹⁵⁶ and in only 1% of colorectal cancer patients when bevacizumab was administered with FOLFOX.¹³⁵

Gastric and GEJ cancers

Ramucirumab can be used for treatment of fluoropyrimidine-resistant or platinum-resistant gastric or GEJ cancer as a single agent or with paclitaxel. Approval of ramucirumab as a single agent was based on a multinational, randomized double-blind trial in 655 patients with previously treated advanced or metastatic disease who were randomized (2 : 1) to ramucirumab or placebo plus BSC. Addition of ramucirumab to paclitaxel significantly improved OS (9.6 months vs 7.4 months, P = 0.017) and PFS (4.4 months vs 2.9 months, P < 0.001).¹⁵⁹

Lung cancer

Ramucirumab in combination with docetaxel was approved for treatment of metastatic NSCLC that had progressed on platinum-containing regimens or anti-EGFR or anti-ALK targeted therapy. Approval of ramucirumab in combination with docetaxel was based on a double-blind, placebo-controlled clinical trial that enrolled 1253 patients with previously treated metastatic NSCLC.¹⁶⁰ Addition of ramucirumab to docetaxel significantly increased OS (10.5 months vs 9.1 months; P = 0.024) and PFS (P < 0.001).

Colorectal cancer

Ramucirumab can be used in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and, fluoropyrimidine-containing regimen. This approval is based on the results of a randomized, double-blind, multinational trial enrolling 1072 patients who were randomly allocated to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab.¹⁶¹ Addition of ramucirumab to FOLFIRI improved OS (13.3 months vs 11.7 months; P = 0.023) and PFS (5.7 months vs 4.5 months; P < 0.001).

Toxicity

Ramucirumab treatment can be associated with fatigue, weakness, hypertension, hyponatremia, diarrhea, and nose bleeds. When combined with paclitaxel or docetaxel, neutropenia, febrile neutropenia, and anemia have been observed. Other rare, but important risks described in product labeling include hemorrhage, arterial thromboembolic events, infusion-related reactions, gastrointestinal obstruction, gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with cirrhosis, and reversible posterior leukoencephalopathy. Hypothyroidism has been observed in patients with colorectal cancer.

Toxicity

Common side effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhea, skin rash, uveitis, hypophysitis, endocrine deficiencies, and inflammation of the intestines (colitis) and hepatitis.¹⁶⁴

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