In the realm of drug development and discovery, initial attention gravitates towards medicines that are first-in-class or first-in-modality. However, it is often the subsequent generation of therapies that vividly demonstrates the true clinical potential of a drug target or pioneering technology.

Credit: Dan Brownsword / Cultura RM / Alamy Stock Photo

The past 12 months saw the approval of many such groundbreaking treatments across the oncology landscape, highlighting the strides in therapeutic innovation that continue to improve the lives of patients with cancer and prolong their survival. From new bispecific antibodies that are redirecting T cells against difficult-to-treat blood cancers to new types of kinase inhibitors, selective estrogen receptor degraders (SERDs) and more, 2023 brought a bevy of oncology drugs to market, along with some massive licensing agreements and pharma acquisitions focused on burgeoning drug platforms.

Amidst these notable gains, however, the field faced some clinical setbacks, with financial challenges and the enduring effects of pandemic-related trial disruptions further impeding the pace of therapeutic advancement. Here are some of the major achievements and stumbles that marked the past year in oncological drug development.

Engagers unleashed

The 2014 approval of the T cell-engaging agent blinatumomab (Blincyto) for the treatment of acute lymphoblastic leukemia was projected to quickly usher in a wave of bispecific antibody therapies for all kinds of cancers. But the ensuing years were marked by more trial failures than successes — and it would take until May to August of this past year, with the marketing authorization of four such drugs in fewer than 90 days, for the promise of cancer bispecifics to begin to be fully realized1.

First came the approvals of epcoritamab (Epkinly) and glofitamab (Columvi), both of which bind the T cell receptor CD3 with one part of their structure and the CD20 receptor found on B cells with another part. In clinical testing, each therapy brought about complete remissions in around 40% of patients with relapsed or refractory diffuse large B cell lymphoma, and with favorable toxicity profiles.

The drugs join the follicular lymphoma-approved therapy mosunetuzumab (Lunsumio), another CD20 × CD3 bispecific granted the regulatory go-ahead in December 2022, as off-the-shelf immunotherapies now available for patients with aggressive lymphomas.

In August, two more CD3-engaging bispecifics were approved, each as treatment options for patients with heavily pre-treated multiple myeloma. Both the GPRC5D-directed talquetamab (Talvey) and the bispecific BCMA-directed elranatamab (Elrexfio) yielded objective responses in around two-thirds of trial participants.

Bispecifics aimed at other myeloma-associated antigens are also in development, with further BCMA × CD3 T cell engagers either approved or nearing the market — all of which led some myeloma specialists to declare that the field is experiencing an “embarrassment of riches”2.

Platform pile-on

Beyond bispecific designs, many large pharmaceutical companies in 2023 rallied behind the engineering strategy of armoring antibodies with therapeutic payloads.

Pfizer acquired Seagen in a US$43 billion deal centered largely on a robust pipeline of antibody–drug conjugates (ADCs). Merck inked one of the largest licensing deals in industry history — worth up to $22 billion — to partner with Daiichi Sankyo on the advancement of three ADCs in various stages of clinical development for different tumor types. Other drug-makers have been lining up smaller ADC-related deals of their own.

Alongside these developments, the industry embraced several other cutting-edge platform technologies this year, including the use of artificial intelligence for drug discovery3 and the application of messenger RNA to build and deploy personalized cancer vaccines4.

The latter strategy passed its first major clinical test in April, when Moderna and its development partner Merck reported the results of a phase 2 randomized trial involving mRNA-4157, an individualized vaccine consisting of an mRNA encoding up to 34 neoantigens, packaged in lipid nanoparticles and administered via injection into the arm. The 157-person study found that adjuvant treatment with a checkpoint inhibitor along with mRNA-4157 helped to lower the risk of death or relapse by 44% in patients with completely resected, high-risk melanoma compared to treatment with the checkpoint-blocking agent alone.

A month later, BioNTech and its development partner Genentech published the findings of a single-arm trial in patients with resectable pancreatic ductal adenocarcinoma, demonstrating the ability of an mRNA vaccine known autogene cevumeran to trigger neoantigen-specific T cell responses and prolong tumor recurrence5. Both mRNA vaccine candidates, now in larger randomized trials, are widely credited with reinvigorating the field of personalized cancer vaccination, and driving investment in other RNA-based therapeutic programs in oncology.

Hitting the target

Efforts to inhibit KRAS, one of the most frequently mutated driver proteins in cancer, continued apace this year following the December 2022 approval of adagrasib (Krazati), a drug that, like sotorasib (Lumakras) before it, works by covalently targeting the G12C-mutant form of KRAS.

This variant is found frequently in lung tumors, a feature that helps explain why Bristol Myers Squibb agreed to pay up to $5.8 billion in October to acquire the manufacturer of adagrasib — Mirati Therapeutics. It is also why further KRAS(G12C)-targeted inhibitors are advancing through clinical development, including one called divarasib that, according to phase 1 data published in August, could be best-in-class6.

Other KRAS mutations are far more common across the cancer spectrum, and there was much progress in 2023 toward broadening the range of targetable variants. Data from first-in-human trials unveiled at oncology meetings this year — some involving drugs directed against the most prevalent mutant form of KRAS, KRAS(G12D); others involving agents designed to broadly inhibit several active states of the cancer driver — showed promising signs of safety and antitumor activity7.

Meanwhile, one of the hottest targets in oncology — the tight junction protein CLDN18.2 that is abnormally overexpressed by many cancers — continues to garner substantial attention from drug developers, with the first CLDN18.2-targeted antibody poised for regulatory approval in early 2024. That antibody, called zolbetuximab, helped to extend the survival of patients with gastric and gastroesophageal junction cancer, researchers reported this year8 — but only by a couple of months.

Rival drugmakers, with their arsenal of monoclonal antibodies, bispecifics, ADCs and chimeric antigen receptor T cell therapies — all geared toward targeting CLDN18.2 — are now motivated by the hope that they can do better9.

Eat-me some humble pie

However, some targets have continued to elude the best efforts of drug developers. In 2023, several trials of magrolimab, the most clinically advanced therapeutic candidate designed to block the CD47 ‘do not eat me’ signal that tumor cells co-opt to shield themselves from macrophages, were shelved for futility, including phase 3 studies in patients with myelodysplastic syndrome (MDS) and TP53-mutated acute myeloid leukemia (AML). Another large AML study was also placed on a partial clinical hold.

Confidence in CD47 as a viable immunotherapy target was further shaken by news this year that Arch Oncology, maker of its own CD47-directed antibody, had shut down operations; that AbbVie had pulled out of a co-development with I-Mab over a different anti-CD47 drug candidate; and that ALX Oncology, the company behind evorpacept, was ending programs of its CD47 inhibitor in MDS and AML.

Still, there was a glimmer of hope for this therapeutic drug class. In October, ALX announced positive interim data from a randomized phase 2 trial of evorpacept in patients with gastric and gastroesophageal junction cancers, leading some to conclude that CD47 inhibition might still hold promise in solid tumors or in combination with other targeted therapies.

Immune checkpoint inhibitors, even as they notched up expanded indications, new routes of administration, and welcomed two new PD-1-blocking monoclonal antibodies — retifanlimab (Zynyz) and toripalimab (Loqtorz) — to their midst this year, also struggled to gain a foothold as treatments for certain cancer types.

In advanced prostate cancer, for example, two phase 3 trials of pembrolizumab (Keytruda) were halted in 2023 after interim analyses failed to show any benefit of adding the PD-1 inhibitor to standard androgen-suppression therapy10. A late-stage trial of the PD-L1 inhibitor atezolizumab (Tecentriq) for recurrent ovarian cancer also ended in failure, and an ovarian cancer study of the PD-1 blocker durvalumab (Imfinzi) returned mixed results, adding benefit only when administered alongside a poly(ADP-ribose) polymerase (PARP) inhibitor.

Firsts off the blocks

Among the array of new cancer therapeutics approved by the US Food and Drug Administration (FDA) in 2023, patients stood to benefit substantially, notably with momelotinib (Ojjaara), a JAK inhibitor that became the first treatment indicated for anemia associated with myelofibrosis, a rare type of blood cancer, and with nirogacestat (Ogsiveo), a gamma secretase inhibitor and the first drug specifically approved for treating desmoid tumors, a rare form of soft tissue sarcoma. In addition, quizartinib (Vanflyta) emerged as the inaugural drug specifically designed to target internal tandem duplications in the FLT3 gene, a common mutation linked to AML.

Contributing to these advancements was pirtobrutinib (Jaypirca), a non-covalent inhibitor of BTK. By binding reversibly to its target, this agent can maintain its efficacy, even in the presence of acquired resistance mutations — thus setting it apart from other BTK-blocking agents11. And in November, the FDA gave the green light to capivasertib (Truqap), the first selective inhibitor of AKT. In phase 3 testing, the addition of capivasertib to SERD therapy helped to delay disease progression among patients with a particular subtype of breast cancer, researchers reported in June12.

Capivasertib joins elacestrant (Orserdu), another therapy approved this year for the same population of patients with ER-positive, HER2-negative breast cancer. As the first oral SERD, elacestrant offers not only convenience advantages but also pharmacological ones over the injectable standard, fulvestrant13.

Brain cancers also witnessed their share of new drug options over the past year. In March, a targeted drug combination comprising dabrafenib (Tafinlar) and trametinib (Mekinist), inhibitors of the BRAF and MEK signaling proteins, respectively, received approval as a first-line therapy for specific pediatric low-grade gliomas. Then in September, an initiative by the FDA known as Project Renewal14 led to a series of new and revised indications for temozolomide (Temodar) for anaplastic astrocytomas. This development marked the second labeling change under the program, following the December 2022 update for the chemotherapy agent capecitabine (Xeloda).