Disease Analysis: NHL: Follicular Lymphoma

Disease Overview

Follicular lymphoma (FL) is an indolent subtype of non-Hodgkin’s lymphoma (NHL) specifically originating from centrocyte and centroblast B cells and usually beginning in the lymph nodes. The disease is among the most common forms of NHL alongside diffuse
large B-cell lymphoma (DLBCL), accounting for approximately 35% of all NHLs.

Latest key takeaways

• Follicular lymphoma (FL) is an indolent subtype of non-Hodgkin’s lymphoma (NHL) specifically originating from centrocyte and centroblast B cells and usually beginning in the lymph nodes. The disease is among the most common forms of NHL alongside diffuse large B-cell lymphoma (DLBCL), accounting for approximately 35% of all NHLs.
• Datamonitor Healthcare estimates that in 2018, there were 70,800 incident cases of follicular lymphoma (FL) worldwide, and expects that number to increase to 76,600 incident cases by 2027.
• Despite being essentially incurable, FL progresses very slowly, meaning that five-year survival rates are relatively high. Treatments are largely intended to drive the disease into remission until recurrence, at which point another round of therapy will be required. While remissions with first-line therapy can be long, there are diminishing returns with each additional line of therapy.
• Since its approval in 1997, most recommended regimens, particularly in the first-line setting, combine the anti-CD20 antibody Rituxan with chemotherapy. Rituximab biosimilars are now also widely available. Rituximab combined with bendamustine (BR) is a popular first-line regimen followed by rituximab combined with Revlimid and R-CHOP.
• Another anti-CD20 antibody, Gazyva, has also found modest success in early lines of therapy.
• Bendamustine, marketed as Bendeka/Treanda/Belrapzo, is a mustard chemotherapy and has the advantage of being more tolerable compared to CHOP. Bendamustine uptake has been strong, being among the first marketed agents shown to improve PFS when combined with anti-CD20 antibodies in both first-line (1L) and 2L therapy.
• The immunomodulator Revlimid combined with rituximab (R2) is approved for 2L+ patients and is an off-label option for 1L patients. While the RELEVANCE trial failed to establish a benefit for R2 compared to rituximab combined with chemotherapy in the 1L setting, it offers a chemotherapy-free option and is supported by an NCCN preferred regimen recommendation. A second Phase III trial, AUGMENT, showed an improvement in PFS for R2 compared to rituximab in the 2L setting and led to its approval.
• Tazverik, a first-in-class EZH2 inhibitor, received accelerated approval in the US (2020) and Japan (2021) for relapsed/refractory patients with an EZH2 mutation in their tumor. Approximately 25% of FL patients have an EZH2 mutation. The US approval specified 3L+ patients while the Japanese approval specified relapsed/refractory patients with no applicable therapy options. In the US, Tazverik is also approved for 2L+ patients with wild-type EZH2 and no alternative treatment options. A confirmatory Phase III trial is evaluating a combination of Tazverik, Revlimid, and rituximab in 2L+ patients with a June 2022 estimated primary completion date (PCD).
• PI3K inhibitors, represented in FL by Aliqopa and Ukoniq in the US, and Zydelig and Copiktra in the EU, have raised toxicity concerns but represent an important treatment option for 3L+ patients. Aliqopa and Ukoniq show more manageable safety profiles and are expected to be joined by next-generation PI3K antagonist zandelisib. Aliqopa is under regulatory review for a label expansion based on its Phase III CHRONOS-3 trial, which evaluated a combination with rituximab for 2L disease. While the PDUFA date was originally 21 December 2021, there has been no update as of February 2022. The Phase III CHRONOS-4 trial is evaluating Aliqopa combined with standard immunochemotherapy (BR or R-CHOP) in 2–4L FL, and the estimated PCD for the trial is April 2022. A regulatory submission for zandelisib for 3L+ FL is expected in 2022.
• Yescarta, approved in the US for 3L disease in March 2021, has become the first CAR-T therapy in FL. It is expected to shortly be followed by Kymriah. Breyanzi is another CD19 CAR-T therapy currently in late-phase development.
• Odronextamab and mosunetuzumab, bispecific T-cell engagers (BiTEs) targeting CD20 and CD3, present an opportunity to improve upon the mechanism of anti-CD20 monoclonal antibodies. Initial accelerated approval will be for 3L+ disease, but confirmatory Phase III trials will evaluate combinations for 2L disease. Regulatory submissions for these two bispecific antibodies are expected in 2022, with mosunetuzumab expected to be first to market.
• In an immunoradiotherapy platform similar to that of Zevalin, Betalutin uses a CD37 antibody conjugated to a radionuclide of lutetium-177 to destroy cancer cells with radiation in a targeted manner. As the first CD37-targeted agent, this approach may be useful for highly refractory patients. With good tolerability and a convenient dosing schedule, Betalutin is being developed for elderly/frail patients who cannot tolerate chemotherapy or some of the newer agents such as CAR-T therapy or bispecific antibodies. However, working with a radioactive product requires specialized centers and staff, and patients may be put off by the idea of a radioactive drug. Such factors limited use of Zevalin and may limit uptake of Betalutin if approved.
• BTK inhibitors include BeiGene’s Brukinsa and AbbVie’s Imbruvica. Imbruvica combined with standard immunochemotherapy (BR or R-CHOP) is being evaluated in a Phase III trial for 2L+ patients, while Brukinsa is being evaluated in combination with Gazyva in a pivotal Phase II trial for 3L+ patients. Data for both trials are expected in Q1 2022.
• Also seeking to position themselves as alternatives to anti-CD19 CAR-Ts in heavily pretreated disease are a pair of developmental anti-CD19 antibodies, Monjuvi and the antibody-drug conjugate Zynlonta. A Phase III trial is evaluating Monjuvi combined with R2 in 2L+ patients, while a pivotal Phase II trial is evaluating Zynlonta monotherapy for 3L+ patients.
• Takeda’s TAK-007 is an off-the-shelf cellular therapy consisting of natural killer cells modified to express an anti-CD19 CAR. In early-phase trials, TAK-007 has demonstrated remarkable efficacy without the development of any major cytotoxic effects such as cytokine release syndrome. TAK-007 is being developed for 3L+ patients but the pivotal trial is still in dose-escalation.
• The overall likelihood of approval of a Phase I indolent NHL (including FL) asset is 16.4%, and the average probability that a drug advances from Phase III is 52.6%; both of these figures are higher than the average seen across oncology indications. Drugs, on average, take 9.6 years from Phase I to approval, which is faster than the 9.7-year average in the overall oncology space.