Innovation in the oncology drug pipeline has led to a record number of FDA approvals in recent years, as investigators and sponsors seek new treatments for the nearly 2 million cancer cases diagnosed in the United States each year.1 In 2022, this trend should continue, as regulators evaluate new therapies and those approved in other indications for unmet needs in the growing, aging cancer community. Below is a roundup of notable drugs in the oncology pipeline that have a Prescription Drug User Fee Act (PDUFA) date scheduled for the first half of 2022.
Ciltacabtagene Autoleucel (Cilta-cel)
Developed as a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy, cilta-cel’s combined findings in its phase 1b/2 CARTITUDE-1 trial (NCT03548207) signal an exciting, potentially lifesaving development for the treatment of adults with heavily pretreated relapsed and/or refractory multiple myeloma (MM). Evidence shows that patients with MM have a poor prognosis if their disease progresses after 3 treatments, with a typical overall survival (OS) of less
than 6 months.2
Marked by novel 2 BCMA–binding domains, Janssen’s cilta-cel was investigated among 97
patients with MM (median age, 61 years; 58.8% male) whose prior lines of therapy ranged from 3 to 18, with a median of 6 treatments. With 88% of patients identified as triple-class refractory and 42% as penta-refractory, CARTITUDE-1 findings reported at last year’s American Society of Hematology (ASH) Annual Meeting and Exposition showed that those
treated with the investigational CAR T-cell therapy had a 12-month progression-free survival (PFS) of 77% (95% CI, 66%-84%) and a 12-month OS rate of 89% (95% CI, 80%-94%).3
Moreover, study participants exhibited an overall response rate (ORR) of 97% and a stringent response rate of 67%, and 93% of patients achieved minimal residual disease. Potential for administration in an outpatient setting was also noted because median onset of cytokine release syndrome (CRS), a common adverse event (AE) in CAR T-cell therapy,
was 7 days after infusion, with 89% not experiencing CRS until day 4. CRS was seen in all but 5 patients, with most cases indicated as grade 1 or 2 and 99% resolving within 14 days. Neurotoxicity was reported in 21% of patients, in which 10% had neurotoxicity of grade 3 or higher. Overall, 6 individuals died due to AEs from treatment.
Following these findings, Janssen and its collaborator, Legend Biotech Corporation, applied for a biologics license application (BLA) for cilta-cel in the treatment of adults with relapsed or refractory multiple myeloma. The application was accepted under priority review in May 2021. Cilta-cel was previously granted breakthrough therapy designation in December 2019 and orphan drug designation in February 2019.4,5
The FDA recently extended cilta-cel’s PDUFA date to February 28, 2022, citing the need for sufficient time in reviewing new information submitted following an FDA request. A November 1 statement said both collaborators had met with the FDA, with no additional clinical data having been requested.6 Additional research on cilta-cel is set to be presented at the 63rd ASH Annual Meeting and Exposition in December 2021, including the following:
• Longer-term follow-up data and new subgroup analysis results from the phase 1b/2 CARTITUDE-1 study
• Adjusted indirect comparison of CARTITUDE-1 patient outcomes relative to standard-of-care therapies in real-world clinical practice from the LocoMMotion study (NCT04035226)
• First data release from cohort B and longerterm follow-up data from cohort A of the
CARTITUDE-2 study (NCT04133636) in earlier lines of treatments
Tislelizumab, an anti–PD-1 immune checkpoint inhibitor, recently had its BLA accepted by the FDA for the treatment of unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic therapy. ESCC is the most common type of esophageal cancer and sixth-leading cause of cancer death worldwide; right now, patients with ESCC typically have a 5-year survival rate of 19.9%. The therapy also has potential to treat myriad oncology disease states as either a monotherapy or in combination with other drugs and is already approved in China for certain patients with non–small cell lung cancer (NSCLC), classical Hodgkin’s lymphoma, and metastatic urothelial carcinoma.
Novartis’ BLA in ESCC marks the first overseas application for the drug; the application is based on findings of the phase 3 RATIONALE 302 trial (NCT03430843) that investigated its use vs chemotherapy as second-line treatment for advanced unresectable/metastatic ESCC. Findings presented at the 2021 American Society of Clinical Oncology (ASCO)
Annual Meeting showed that tislelizumab met its primary end point of improvement in OS ( median OS, 8.6 vs 6.3 m) and exhibited a 30% decreased risk of death (HR, 0.70; 95% CI, 0.57-0.85; P = .0001), compared with investigator-chosen standard chemotherapy
(paclitaxel, docetaxel, or irinotecan).7
The treatment is designed to have reduced binding to Fc¦ receptors, a potential mechanism
of resistance associated with other PD-1 inhibitors. In preclinical studies, binding to Fc¦ receptors on macrophages has been shown to compromise the antitumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. However, the clinical impact of these features is not yet known.
The BLA currently has a PDUFA target action date of July 12, 2022. If approved, the drug would compete with other checkpoint inhibitors, including Bristol Myers Squibb’s (BMS) nivolumab (Opdivo) and Merck’s pembrolizumab (Keytruda), both approved as first-line treatments in combination with chemotherapy for patients with ESCC regardless of PD-L1 status.8 Novartis is also investigating tislelizumab as a monotherapy and combination
therapy for other indications, including in NSCLC, gastric cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, with broad potential in several other solid tumors.9,10
As the first investigational therapy in a phase 3 trial to show a survival benefit in patients with the rare and potentially fatal metastatic uveal cancer, tebentafusp, a bispecific T-cell engager (BiTE), functions by simultaneously binding to lymphocyte CD3 receptors and gp100 antigens expressed on cancer cells—a novel process of bringing T cells to tumor cells that has not been explored in prior solid tumor indications. Based on findings from the
IMCgp100-202 trial (NCT03070392) presented at the American Association for Cancer Research Annual Meeting 2021,11 Immunocore’s tebentafusp was granted BLA approval with priority review by the FDA and marketing authorization by the European Medicines Agency in the treatment of patients with HLA-A*02:01–positive metastatic uveal melanoma.12
Notably, patients treated with the experimental agent over a median follow-up of 14.1 months were associated with a median OS of 21.7 months (95% CI, 18.6-23.6), compared with investigator’s choice of pembrolizumab, ipilimumab (Yervoy), or dacarbazine at 16.0 months (95% CI, 9.7-19.4; stratified HR, 0.51; 95% CI, 0.37-0.71; P < .0001). With no current standard-of-care options available for patients with uveal melanoma who have metastatic
disease, the 1-year OS rate of 73.2% observed in the tebentafusp arm of the trial marks a potential therapeutic breakthrough; previously, patients with this condition in frontline trials have garnered OS rates of approximately 50%.
Moreover, approval of tebentafusp could spark major innovation in immuno-oncology, specifically regarding use of BiTEs vs PD-1 inhibitors in solid tumors. Currently, development of BiTEs remains a largely experimental segment in immuno-oncology, with only 1 such drug, blinatumomab (Blincyto), approved in leukemia.
Treatment-related AEs occurred in all patients treated with tebentafusp, in which 45% had severe grades of 3 or 4. Treatment-related discontinuations were 2% in the experimental arm vs 4% in the investigator’s choice arm, and no treatment-related deaths occurred.
The BLA is being reviewed under the Real-Time Oncology Review pilot program, which is designed to expedite the delivery of tolerable and efficacious treatments for patients with cancer, as well as under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in partner countries that have requested participation. The PDUFA target action date for tebentafusp is currently scheduled for February 23, 2022.
Although no BLA has been submitted for pirtobrutinib, findings of the phase 1/2 BRUIN clinical trial (NCT03740529) have shown promising efficacy and safety for Eli Lilly and Company’s investigational, highly selective, noncovalent Bruton tyrosine kinase (BTK) inhibitor in the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and other B-cell malignancies.
Results published in The Lancet13 reported that pirtobrutinib was investigated in 323 patients with relapsed or refractory disease, including those with CLL or small lymphocytic leukemia (SLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia,
and other non-Hodgkin lymphomas. In patients with CLL/SLL evaluable for response (n =
139), ORR was shown to be 63%; more notably, findings in those treated with a previous covalent BTK inhibitor suggest a potential opportunity to address a growing unmet need for alternative therapies.
Currently, 5-year discontinuation rates with the BTK inhibitor of ibrutinib are 41% in the frontline setting and 54% for those with relapsed/refractory disease. Among the 121 patients with CLL/SLL who were treated with a previous covalent BTK inhibitor (median previous lines of treatment, 4), ORR was 62%. This comprises a 47% partial response (PR) rate and a 15% PR rate with lymphocytosis, according to dose-escalation/dose-expansion findings presented during the Society of Hematologic Oncology 2021 Annual Meeting.14
Moreover, similar response rates were found in patients with CLL who had previous covalent BTK inhibitor resistance (ORR, 67%) and covalent BTK inhibitor intolerance (ORR, 52%), as well as those with BTK C481 mutations (ORR, 71%) and BTK wild-type (ORR, 66%) disease. Cases of progressive disease in CLL following administration of covalent BTK inhibitors have been found most frequently in patients with BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition.
Further findings showed an ORR of 52% in patients with MCL previously treated with covalent BTK inhibitors. The most common AEs overall included fatigue (20%), diarrhea (17%), and contusion (13%), and the most common grade 3 or higher AE was neutropenia (10%).
Of the 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression-free to date. In fact, data have also shown that the ORR with pirtobrutinib increases over time, with those who had been on treatment for at least 10 months exhibiting an ORR of 86%. In addition to the phase 1/2 BRUIN trial, a series of phase 3 studies investigating pirtobrutinib are planned to be initiated in 2021, including 3 in CLL and one in MCL.
New Indications for FDA-Approved Therapies
Along with the new therapies poised to enter the oncology market in 2022, there are several
FDA-approved cancer therapies that may be approved for new indications.
CEMIPLIMAB-RWLC. With 3 previous FDA approvals, most recently as a monotherapy for patients with first-line advanced NSCLC with PD-L1 expression,15 the PD-1 inhibitor cemiplimab-rwlc (Libtayo) had its supplemental BLA accepted by the FDA under priority review in the treatment of patients with recurrent or metastatic cervical cancer whose
disease progressed on or after chemotherapy.16
Supported by positive results of the phase 3 EMPOWER-Cervical 1 trial (NCT03257267), in which the drug demonstrated significant improvements in OS, PFS, and ORR, compared with chemotherapy, its potential indication for advanced cervical cancer would provide another therapeutic intervention for which limited options exist.17 Cervical cancer is the fourth-leading cause of cancer death in women worldwide.16 The PDUFA date is scheduled for January 30, 2022. Regeneron’s cemiplimab-rwlc has also shown promise in a phase 1 study of patients with advanced melanoma when paired with fianlimab, an anti–LAG-3 monoclonal antibody, with efficacy found highest in patients who had not received anti–PD-1 drugs previously.18
RELATLIMAB AND NIVOLUMAB. Another therapy combination with potential in the treatment of melanoma is BMS’ relatlimab and nivolumab. This combination recently had its BLA accepted under priority review for the treatment of adults and pediatric patients with unresectable or metastatic disease, with a PDUFA date scheduled for March 19, 2022.19
Based on findings of the phase 2/3 RELATIVITY-047 trial (NCT03470922), the fixed-dose combination, administered as a single infusion, was associated with a statistically significant and clinically meaningful PFS benefit vs standard of care anti–PD-1 monotherapy in metastatic melanoma. Primary results presented at ASCO 2021 showcased relatlimab as
the first LAG-3–blocking antibody to demonstrate a clinical benefit for patients with phase 3 data.20
If approved, the combination therapy would provide an alternative to the pairing of nivolumab and ipilimumab (Yervoy), another immunotherapeutic agent that is effective but has been linked with AEs that cause discontinuation or preference for monotherapy with nivolumab.21
NIVOLUMAB AND IPILIMUMAB. The pairing of BMS’ nivolumab and ipilimumab, as well as nivolumab in combination with fluoropyrimidine-containing and platinum-containing chemotherapy, is also being explored in the treatment of unresectable advanced or metastatic ESCC, with both sBLAs having been approved by the FDA following significant improvement in OS observed in the CheckMate-648 study (NCT03143153). The PDUFA date is scheduled for May 28, 2022.22
1. Jeremias S. Cancer treatments, orphan drugs, gene therapies represent big areas to watch in specialty drug pipeline. The American Journal of Managed Care®. October 20, 2021. Accessed November 15, 2021. https://bit.ly/3Cqb286
2. Caffrey M. CAR T-cell therapies old and new: cilta-cel wows in multiple myeloma; axi-cel shows 44% OS at 4 years in LBCL. The American Journal of Managed Care®. December 5, 2020. Accessed November 15, 2021. https://bit.ly/3oEbKcT
3. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. Published correction appears in Lancet. 2021;398(10307):1216
4. U.S. Food and Drug Administration grants BCMA CAR-T cilta-cel priority review for the treatment for relapsed/refractory multiple myeloma. News release. Legend Biotech. May 26, 2021. Accessed November 15, 2021. https://bwnews.pr/3qKHIXs
5. U.S. Food and Drug Administration grants Breakthrough Therapy Designation for JNJ-68284528, an investigational BCMA CAR-T cell therapy. News release. Legend Biotech. December 6, 2019. Accessed November 15, 2021. https://bit.ly/3kOr4Cz
6. Legend Biotech announces extension of PDUFA date for cilta-cel. News release. Legend Biotech. November 1, 2021. Accessed November 15, 2021. https://bwnews.pr/3FpB117
7. Shen L, Kato K, Kim SB, et al. RATIONALE 302: Randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4012. doi:10.1200/
8. Taylor P. First FDA filing for Novartis’ latecomer PD-1 drug tislelizumab. Pharmaphorum. September 13, 2021. Accessed November 15, 2021. https://bit.ly/2Z1zqPK
9. Novartis strengthens oncology pipeline with successful closing of tislelizumab in-licensing. News release. Novartis. February 26, 2021. Accessed November 15, 2021. https://bit.ly/30AxP3x
10. Collins J. Tislelizumab plus chemotherapy elicits PFS benefit in advanced squamous NSCLC. OncLive®. September 8, 2021. Accessed November 15, 2021. https://bit.ly/3oAvgqQ
11. Immunocore presents phase 3 data comparing tebentafusp with investigator’s choice in the clinical trial plenary session at the American Association for Cancer Research 2021 Annual Meeting. News release. Immunocore. April 12, 2021. Accessed November 15, 2021. https://bit.ly/3kO6diW
12. Immunocore announces that U.S. Food and Drug Administration and European Medicines Agency accept Biologics License Application and Marketing Authorization Application for tebentafusp in metastatic uveal melanoma. News release. Immunocore. August 24, 2021. Accessed November 15, 2021. https://bit.ly/30xvGGv
13. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
14. Coombs CC, Pagel JM, Shah NN, et al. Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Presented at: SOHO 2021 Annual Meeting; September 8-11, 2021; virtual. Abstract CLL-039.
15. McNulty R. FDA approves cemiplimab for first-line advanced NSCLC with PD-L1 expression. The American Journal of Managed Care®. February 22, 2021. Accessed November 16, 2021. https://bit.ly/325lxRv
16. FDA accepts Libtayo (cemiplimab-rwlc) for priority review for advanced cervical cancer. News release. Regeneron. September 28, 2021. Accessed November 16, 2021. https://bit.ly/3r1KjwD
17. Positive phase 3 Libtayo (cemiplimab) results in advanced cervical cancer presented at ESMO Virtual Plenary. News release. Regeneron. May 12, 2021. Accessed November 16, 2021. https://bit.ly/3x081tR
18. Hamid O, Wang D, Kim TM, et al. Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9515. doi:10.1200/JCO.2021.39.15_suppl. 9515
19. U.S. Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for LAG-3-blocking antibody relatlimab and nivolumab fixed-dose combination as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. September 20, 2021. Accessed November 16, 2021. https://bit.
20. Lipson EJ, Tawbi HAH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):950. doi:10.1200/JCO.2021.39.15_suppl.9503
21. Buntz B. 25 promising pipeline drugs. Drug Discovery & Development. May 20, 2021. Accessed November 16, 2021. https://www.drugdiscoverytrends. com/promising-pipeline-drugs/
22. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + chemotherapy for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. September 27, 2021. Accessed November 16, 2021.