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 2021, there were 72,800 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, to be 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 progression-free survival (PFS) when combined with anti-CD20 antibodies in both first-line (1L) and second-line (2L) therapy. More recently, competition from Revlimid has cut into bendamustine sales in the 2L setting.
• 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, which led to its approval.
• Tazverik, a first-in-class EZH2 inhibitor, received accelerated approval in the US (2020) and in 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 third-line or later (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 March 2026 estimated primary completion date (PCD).
• PI3K inhibitors, represented in FL by Aliqopa in the US, and Zydelig and Copiktra in the EU, have raised toxicity concerns which will limit their use. Aliqopa has an opportunity for a label expansion based on its Phase III CHRONOS-3 trial, which evaluated a combination with rituximab for 2L disease. An sNDA supported by CHRONOS-3 was withdrawn, with Bayer saying it is collating additional data and conducting further analyses. 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 February 2023. Bayer may be waiting for OS data from CHRONOS-3 as well as results from the CHRONOS-4 trial before resubmitting.
• Zandelisib is differentiated from existing PI3K inhibitors by forming a covalent bond with the PI3K delta subunit, making it an irreversible inhibitor. With the increased scrutiny being given to PI3K inhibitors, the FDA has requested that a regulatory submission be supported by a randomized trial. A Phase III pivotal trial, COASTAL, is evaluating zandelisib combined with rituximab for 2L+ FL and has an estimated PCD of April 2026.
• There are currently two CD19-directed CAR-T therapies approved for FL. Yescarta is approved in the US (March 2021) and Europe (June 2022), while Kymriah is approved in the US (May 2022), Europe (April 2022), and Japan (August 2022). All approvals were for 3L+ FL, except Kymriah’s Japanese approval which was for 2L+ FL. Comparing Yescarta and Kymriah, a KOL favored Kymriah for its low rate of grade 3/4 cytokine release syndrome (CRS). Overall, the KOL was cautious about using CAR-Ts as he would like to confirm that CRS rates remain low in an older cohort that is more representative of the 3L+ population. A third CAR-T therapy, Breyanzi, is earlier in its development, with the pivotal Phase II TRANSCEND FL trial having an estimated PCD of July 2024. All three therapies have demonstrated remarkable efficacy in clinical trials and have the advantage of requiring just a single infusion. These qualities should allow CAR-Ts to play an important role in the relapsed/recurrent FL landscape, although they come with the tradeoff of being time-consuming and expensive to prepare and administer, as well as being unsuitable for especially frail patients.
• Epcoritamab, odronextamab, and Lunsumio, bispecific T-cell engagers (BiTEs) targeting CD20 and CD3, present an opportunity to improve upon the mechanism of anti-CD20 monoclonal antibodies. With off-the-shelf availability and no need for a course of lymphodepleting chemotherapy, they are expected to be preferred over CAR-T therapy. Lunsumio was approved in the EU for 3L+ FL in June 2022, and is under regulatory review in the US with a PDUFA date of December 2022. Regulatory submissions for odronextamab are expected before the end of 2022 following the presentation of pivotal results at ASH 2022. Epcoritamab is differentiated from the other two BiTEs by its subcutaneous formulation. A pivotal Phase II trial, EPCORE, is enrolling 3L+ FL patients, and the estimated PCD is October 2023. These BiTEs are expected to play an important role in the 3L+ setting. They will also have an opportunity for approval for an earlier setting supported by confirmatory Phase III trials in 2L+ disease. CELESTIMO is evaluating mosunetuzumab combined with Revlimid, while EPCORE FL-1 is evaluating epcoritamab in combination with the R2 regimen. The two trials have estimated PCDs of May 2029 and December 2029, respectively. Regeneron has indicated that it expects to initiate a confirmatory Phase III program evaluating an odronextamab combination before the end of 2022.
• BTK inhibitors include BeiGene’s Brukinsa and AbbVie’s Imbruvica. Imbruvica is being evaluated in two Phase III trials: SELENE is evaluating Imbruvica combined with standard immunochemotherapy (BR or R-CHOP) for 2L+ patients, with data expected before the end of 2022, while PERSEPECTIVE is evaluating Imbruvica combined with rituximab compared to rituximab alone in 1L patients. The estimated PCD for PERSPECTIVE is June 2026, and if the trial is positive, it may offer a chemotherapy-free option for 1L patients. Brukinsa has shown a significantly improved safety profile compared to Imbruvica in head-to-head trials in CLL Waldenström macroglobulinemia. ROSEWOOD, a pivotal, randomized Phase II trial, evaluated Brukinsa + Gazyva in 3L+ FL patients and met its primary endpoint with an overall response rate of 68%. If approved, the Brukinsa + Gazyva combination will offer a chemotherapy-free option combination for 3L+ patients. With BiTEs and CAR-T therapies dominating the 3L setting, Datamonitor Healthcare expects Brukinsa to be used mostly in the smaller 4L+ setting.
• Another anti-CD19 therapy being developed for FL is the monoclonal antibody Monjuvi, with a Phase III trial evaluating Monjuvi combined with R2 in 2L+ patients. The trial has an estimated PCD of February 2024, with data expected in H2 2023.
• 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 CRS. TAK-007 is being developed for 3L+ patients, but its pivotal trial is still in the dose escalation phase.
• The overall likelihood of approval of a Phase I FL asset is 19%, 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 10.0 years from Phase I to approval, compared to 9.9 years in the overall oncology space.