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Expert Critique

FROM THE ASCO Reading Room

Adi J. Klil-Drori Clinical fellow Sunnybrook Health Sciences Centre

Antibody-drug conjugates (ADCs) are essentially chemotherapy coupled with a homing device to target cells, a monoclonal antibody. To date, ADCs have been approved only for use in hematologic malignancies. The first ADC was gemtuzumab ozogamicin (GO), granted accelerated approval by the Food and Drug Administration (FDA) in 2000 for the treatment of CD33-positive acute myeloid leukemia and then voluntarily withdrawn in 2010 because of a single negative trial (more on GO in Rowe and L枚wenberg, Blood, 2013); GO was re-approved by the FDA in 2017. More recent approvals were for inotuzumab ozogamicin for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (2017) and brentuximab vedotin for R/R (2011) and untreated (2018) Hodgkin lymphoma as well as R/R (2011) and untreated (2018) anaplastic large cell lymphoma (and other CD30-positive peripheral T-cell lymphomas).

What appears to be the next approved ADC is polatuzumab vedotin (pola), a CD79a conjugate, which was granted priority review in February 2019 for the treatment of R/R diffuse large B-cell lymphoma (DLBCL) in combination with bendamustine (B) and rituximab (R). This review is based on the results of the GO29365 study, a phase Ib/II trial which included patients with R/R DLBCL (Blood 2018 132:1683). The randomized phase II portion of the trial compared pola-BR with BR alone. Treatment with pola-BR was superior to BR as it relates to complete remission rates (40% vs 18%) and overall survival (12.4 vs 4.7 months).

An earlier trial, the ROMULUS study, was recently published in Lancet Hematology (Morschhauser 2019). This study was a phase II randomized trial including treatments with R-pola or R-pimatuzumab (another ADC). Results showed a positive signal for efficacy in relapsed DLBCL patients, of whom 88% had objective response with R-pola. However, the dose used in ROMULUS was higher than in GO29365 (2.4 mg/m2 vs 1.8 mg/ m2). Thus, the excess of peripheral neuropathy (36% of DLBCL with R-pola, half of whom discontinued the drug) may deter the sponsor from pursuing this dose further. As evidenced, in the POLARIX trial (NCT03274492), a phase III trial investigating pola in untreated DLBCL patients, the lower dose was chosen.

Full Critique

Recent data on antibody-drug conjugates in patients with non-Hodgkin lymphomas continues to be "promising," but this class of drugs must clear an important hurdle to deliver on that promise, researchers said.

Rituximab-based therapy has improved outcomes in non-Hodgkin lymphoma, but additional therapies like antibody-drug conjugates (ADCs) are needed, especially for high-risk and relapsed patients, Annalisa Chiappella, MD, and Umberto Vitolo, MD, both of the University of Health and Science Hospital in Torino, Italy, wrote in a commentary in .

Approximately 50% of patients with follicular lymphoma and 35-40% of patients with diffuse large B-cell lymphoma still relapse at 10 years, they noted. "The prognosis of high-risk patients relapsed or refractory to chemotherapy is unsatisfactory, and the choice of an adequate treatment remains an unmet clinical need."

Median survival of patients with relapsed or refractory diffuse large B-cell lymphoma is approximately 9-12 months with rituximab-based therapy. For relapsed or refractory follicular lymphoma, the estimated progression-free survival is a median 11 months, said Franck Morschhauser, MD, PhD, of the Regional University Hospital of Lille in France, and colleagues, in the that Chiappella and Vitolo wrote about.

ADCs are poised to improve those outcomes, the team said. "ADCs provide targeted drug delivery to tumors to broaden the therapeutic index of a cytotoxic agent ... and have the potential to increase intracellular concentrations of the cytotoxic agent, while sparing tissues that do not express the target."

In the time since the first approval of gemtuzumab ozogamicin (Mylotarg; CD33 targeted), two additional ADCs have been approved for hematologic cancers -- brentuximab vedotin (Adcetris; CD30 targeted) and inotuzumab ozogamicin (Besponsa; CD22 targeted).

Brentuximab vedotin is approved for two rare non-Hodgkin lymphomas -- primary cutaneous anaplastic large cell lymphoma and CD30-expressing mycosis fungoides -- in addition to other indications. Both brentuximab vedotin and inotuzumab ozogamicin are being studied in patients with more common non-Hodgkin lymphomas and are being developed for these indications, Morschhauser and co-authors noted.

ADCs in development include the following:

• Coltuximab ravtansine and denintuzumab mafodotin, both targeting CD19

• SGN75 (targeting CD70)

• Polatuzumab vedotin (targeting CD79b)

• Pinatuzumab vedotin (targeting CD22)

"All of these ADCs are currently in development for non-Hodgkin lymphoma, but with the exception of brentuximab vedotin, none are currently available for the treatment of non-Hodgkin lymphoma," Morschhauser and colleagues said.

Polatuzumab and Pinatuzumab Vedotin

The team recently evaluated the use of polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) combined with rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Both were conjugated to the microtubule inhibitor monomethyl auristatin.

In the phase II open-label study, 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were randomized to receive either R-pola or R-pina every 21 days until disease progression or unacceptable toxicity, for up to 1 year. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%) achieved an objective response and 11 (26%) had a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%) had an objective response, and eight (21%) had a complete response.

Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%) achieved an objective response, and one (5%) had a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%) had an objective response, and nine (45%) had a complete response.

In the diffuse large B-cell group, grade 3-5 adverse events occurred in 79% of patients who received R-pina and 77% of those on R-pola. In patients with follicular lymphoma, grade 3-5 events occurred in 62% of those on R-pina and 50% of those on R-pola. The most common adverse events were neutropenia, anemia, hyperglycemia, and diarrhea.

"Data from this study support both R-pina and R-pola as potentially clinically meaningful treatment options for patients with B-cell non-Hodgkin lymphoma. In particular, observed outcomes in refractory diffuse large B-cell lymphoma appear promising given this difficult-to-treat population," Morschhauser's group wrote.

They noted, however, that the study's sponsor, F. Hoffman La-Roche, has chosen only polatuzumab vedotin for continued study in non-Hodgkin lymphoma. The decision "was based on a comprehensive assessment on an overall benefit-risk ratio qualitatively favoring R-pola and the numerically longer duration of response observed with R-pola, including in patients with high-risk refractory diffuse large B-cell lymphoma," the researchers said. "Furthermore, CD79b is a novel target, distinguishing it from CD22, for which therapies including other ADC and CAR-T are currently in development."

Chiappella and Vitolo, commenting on the study, said: "Considering the clinical characteristics of the patients enrolled ... [heavily pretreated, the majority refractory to the last treatment], the data presented by Morschhauser and colleagues are promising, with a duration of response of just over 1 year in diffuse large B-cell lymphoma and of 9 months in follicular lymphoma."

"The results were especially encouraging given the rates of toxicity reported with ADCs in previous studies," the editorial continued. "The safety profile of pola is manageable, although the proportion of patients who had peripheral neuropathy might be a matter of concern. While awaiting future studies, pola might represent a treatment option in the modern era."

ADCs and Toxicity

Antibody-drug conjugates have proven to be more toxic than expected, and this has been an obstacle in their development, Steven Coats, PhD, a scientist at AstraZeneca, and colleagues said in .

Theoretically, the conjugates should be less toxic than non-targeted therapies. "Antibody drug conjugates were initially designed to leverage the exquisite specificity of antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving the therapeutic index (the ratio between the toxic dose and the dose at which the drug becomes effective)," Coats and co-authors explained. "Unfortunately, the greatest challenge to date for developing ADCs is a therapeutic index far narrower than expected."

The clinical development of more than 50 antibody-drug conjugates has been halted, and for more than 20 of these, the reason was a poor therapeutic index, Coats, et al. wrote. "A narrow therapeutic window limits the dose that can be achieved, often resulting in toxic effects occurring before an ADC reaches its maximally efficacious dose. Despite a clear clinical benefit being demonstrated for all four approved ADCs, the toxicity profiles are comparable to those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mechanism of activity of the cytotoxic warhead."

Nevertheless, the enthusiasm for developing ADCs has not been dampened, the authors added, noting that researchers are exploring ways to overcome the problem, including alternative dosing schedules and improvements in antibody, linker, and warhead technologies.

"While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs," the team wrote. "Approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and two to three novel ADCs are likely to be approved within the next few years."