The landscape of treatment for relapsed/refractory follicular lymphoma (R/R FL) has seen significant advancements with the introduction of T-cell directed therapies such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies. While these therapies have improved outcomes for many patients, there remains a critical need for new chemotherapy-free treatment options that not only improve response rates but also maintain the quality of life throughout the treatment journey. 

Golcadomide (GOLCA), a potential first-in-class oral CELMODTM agent, emerges as a groundbreaking therapeutic candidate in the fight against non-Hodgkin lymphoma, with its unique mechanism that sets it apart from traditional therapies. In addition, its oral administration is one of the primary benefits, which offers a more convenient and less invasive option compared to intravenous therapies.  Bristol Myers Squibb's acquired Celgene in 2019, adding Golcadomide to its pipeline. Golcadomide degrades targeted proteins to produce dual immunomodulatory and direct cell-killing antitumor activity. Golcadomide co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, which are crucial to B-cell malignancy development,' resulting in deep, rapid, and extensive tumor killing independent of cell of origin, and enhanced immunostimulatory activity.

The company has previously reported promising efficacy with a predictable and manageable safety profile of golcadomide monotherapy and combined with rituximab in patients with R/R diffuse large B-cell lymphoma (DLBCL). During the EHA 2024 Congress, the efficacy and safety results from the CC-99282-NHL-001 trial (NCT03930953) for golcadomide rituximab in patients with R/R follicular lymphoma were presented. Median follow-up was 21 months in patients treated with golcadomide monotherapy and 6 months in patients treated with golcadomide + rituximab. 

• Overall response rate (ORR) was 70% in patients treated with golcadomide monotherapy and 79% in patients treated with golcadomide + rituximab. 

• ORR was 100% in patients treated with golcadomide at 0.4 mg + rituximab, with complete response (CR) rate of 70%. 

• Responses were seen in patients including those with prior exposure to lenalidomide or CAR T cell therapies. Responses were seen early, with median time to response of 2 months. 

• Median duration of response (DOR) in patients treated with golcadomide monotherapy was 14.6 months. 

• In patients treated with golcadomide + rituximab, 89% of patients who achieved a response remained in response at time of data cutoff. 

Golcadomide induced deep and sustained dose-dependent degradation of target substrates Ikaros and Aiolos as monotherapy and in combination with rituximab. Golcadomide + rituximab increased the immunomodulatory effects of golcadomide in patients with follicular lymphoma.

Talking about safety, neutropenia emerged as the most prevalent treatment-related adverse event (TRAE) associated with golcadomide, although the occurrence of febrile neutropenia was infrequent. Non-hematological adverse events, including fatigue, diarrhea, and rash, were mostly of low grade. Importantly, there were no treatment-emergent adverse events (TEAEs) related to golcadomide that led to discontinuation of the study drug. Overall, dose reductions were rare, with neutropenia being the primary reason for such adjustments. Dose interruptions were mainly attributed to hematological adverse events or infections. Granulocyte colony-stimulating factor (G-CSF) was administered to 67% of patients receiving golcadomide monotherapy and to 41% of patients on golcadomide combined with rituximab, predominantly for the treatment or prevention of Grade 3 or higher neutropenia.

Conclusion 

With CELMoDs, BMS is expanding into the lymphoma segment in addition to multiple myeloma. Golcadomide has entered into Phase III trial for high Risk 1L Large B-cell Lymphoma (GOLSEEK-1 study; NCT06356129). In addition to this, the company is exploring this CELMoD in Phase I/II in Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL). BMS is also planning to initiate a Phase II GOLSEEK-2 study (NCT06425302) to assess the efficacy and safety of golcadomide in combination with rituximab in participants with newly diagnosed advanced stage FL. The expected start date of the study is August 3, 2024. 

The development of Golcadomide represents a significant step forward in the treatment of NHL, especially for patients with R/R disease who have limited options after conventional therapies fail. Its unique mechanism of action, oral administration, and dual antitumor and immunomodulatory activities distinguish it from existing therapies. 

The Phase I/II study demonstrated that both golcadomide monotherapy and golcadomide in combination with rituximab were well tolerated, with no new safety signals emerging. At the 0.4 mg dose of golcadomide + rituximab, the ORR reached 100%. Responses were observed even in patients who had previously been treated with lenalidomide and/or CAR T-cell therapies. The study is ongoing, with patient enrollment continuing in the monotherapy and golcadomide + rituximab combination expansion cohorts in R/R FL. 

BMS also presented data from CC-220-DLBCL-001 study (NCT04884035) investigating Golcadomide plus R-CHOP in untreated aggressive B-cell lymphoma (BCL) at EHA 2024 congress (Abstract #S235). The study showed that Golcadomide + R-CHOP demonstrated a manageable safety profile, and the addition of golcadomide to R-CHOP did not compromise the delivery of curative treatment. This combination resulted in high rates of durable Complete metabolic responses (CMRs) irrespective of cell-of-origin (COO), with promising 12-month PFS rates in the overall and HR populations. This data support the on-going randomized phase III GOLSEEK-1 trial.