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During the first quarter of each year, we write a retrospective on the previous year’s oncology market, outlining the major events and developments, as well as describing why we think they’re important.  Of course, looking back can be a helpful exercise, but looking forward is more fun.  So, our other tradition is to gaze into our crystal ball and identify the trends that we think will shape the market over the next 12 months and beyond.  We’ve recently done that, and this article is the result.

As we peer into the near-term future, we have identified four key developments to watch for in 2024:

  1. KRAS will kick into “high gear.”
  2. CAR-Ts will focus on manufacturing and the move to outpatient treatment.
  3. Radiopharmaceuticals will grow further, with expanded emphasis on alpha emitters.
  4. Targeted protein degradation will finally “arrive.”

Now, it’s time to dig into the details of each and see how things are likely to progress in the coming months.

KRAS will kick into “high gear.”

We think 2024 will be the year when KRAS will kick into the next gear.  We realize that LUMAKRAS®/LUMYKRAS® (sotorasib) and KRAZATI® (adagrasib), the two approved KRAS G12C inhibitors, have both faced recent commercial and clinical challenges.  LUMAKRAS®/LUMYKRAS® (sotorasib) only did $52 million on Q3 of 2023. KRAZATI® (adagrasib) generated $16.4 million for the three months ended September 30, 2023 and $36.1 million for the nine months ended on the same date.

Clinical issues have also plagued the programs. In October 2023, the FDA’s Oncologic Drugs Advisory Committee (ODAC) found that the progression-free survival (PFS) data from the CodeBreaK 200 trial for sotorasib (NCT04303780) could not be reliably interpreted. Following this, the FDA rejected the supplemental new drug application (sNDA) for sotorasib for patients with previously treated locally advanced or metastatic KRAS G12C-mutated non–small cell lung cancer (NSCLC). The FDA issued a complete response letter and issued a new post-marketing study to be completed no later than February 2028. They did, however, let the drug’s accelerated approval status remain in place. As a reminder, accelerated approval was granted in May 2021 to sotorasib in this intent-to-treat (ITT) population, along with two companion diagnostic devices, representing the first approval for a KRAS directed therapy.

Despite the challenges, we think the KRAS story is only getting started. In a great presentation at Stanford Cancer Institute, Dr. David Hong compares the G12C inhibitors to the breaking of the 4-minute mile, and that after the breaking of the “undruggability” myth around KRAS, we are likely to see continued innovation.

One of the immediate next steps will be combinations with approved KRAS G12C agents. Both sotorasib and adagrasib are now involved in combination studies:

  1. The CodeBreak-101 study (sotorasib) has around 10 different cohorts. Promising data for sotorasib and panitumumab was presented earlier this year.
  2. The KRYSTAL-1 study with adagrasib is similar. One of the studies we are following is the Phase 3 KRYSTAL-10 study, which should read out in 2024 combining adagrasib with cetuximab in colorectal cancer (CRC).

After G12C, the next mutant-specific inhibitor class is likely to be G12D. There has already been some interesting preclinical data from Mirati’s asset, MRTX1133 in this space. Another sign of increasing interest is Jazz’s recently signed deal with Redx for—among other things—a G12D inhibitor.

There has also been a lot of interest in pan-RAS inhibitors, as RMC-6236 and others are emerging. They have shown some compelling early clinical data.  Durability is still short, and we await more data in 2024. Interestingly, the sponsor, Revolution Medicines has ” indicated that based on “encouraging data trends thus far for RMC-6236, planning is underway for one or more single agent pivotal clinical trials potentially to begin in 2024.”

CAR-Ts will focus on manufacturing and the move to outpatient treatment.

CAR-T therapies have generally matured over the last few years, but they appear to be hitting a bit of a plateau. Part of the reason is related to some high-profile concerns about safety issues. However, the expert consensus is that the benefits still outweigh the risks for these therapies, and we agree with that assessment.

Other well-known challenges with CAR-T therapies relate to infrastructure and manufacturing.  In fact, a recent report outlined these issues, saying that CAR-T therapies are facing an “infrastructure reality check,” owing to both referral barriers from the community and an infrastructure bottleneck at hospitals.

Overall, 2024 is likely to be a year of consolidation for CAR-T therapies, and one focused on further improving manufacturing dependability and overall safety, with an eye on moving them to the outpatient setting. We expect a fair amount of push from the market leaders as well as upstarts on these issues throughout the year.

Faster Manufacturing

Late in 2023, we noticed a lot more activity on the manufacturing front. Novartis’ T-Charge platform and BMS’ NEX-T platform are a couple of the “Big Pharma” approaches that have received attention recently.  In addition, Gracell has its “FasTCAR-T” platform that promises to reduce manufacturing time from weeks to mere days.

Novartis recently struck a deal with Legend Biotech for rights to the DLL3-directed project LB2102, which the Swiss firm says it might take forward with the Novartis T-Charge production technology. Novartis also uses T-Charge in rapcabtagene autoleucel, an anti-CD19 Car-T project, and PHE885, which hits BCMA. Bristol Myers Squibb is applying NEX-T to BMS-986354 and BMS-986353, which are CARs versus BCMA and CD19 respectively. Gracell’s GC012F, an anti-BCMA x CD19 bispecific CAR, uses FasTCAR and is being developed for relapsed refractory and front-line maintenance multiple myeloma, as well as lupus. Not to be outdone, KITE announced in January that they received approval for their new process.

We think there will be a continuous drip of updates from these new-fangled manufacturing approaches in 2024. The one caution will be in extrapolating some of these promising manufacturing improvements to the real-world setting. The final proof will be in the pudding, based on what the true vein-to-vein times and out of spec rates are on a broad scale.

Likely as a nod to the excitement for these approaches, and their potential to expand CAR-Ts’ reach and impact, AstraZeneca bought Gracell late last year. AZ has generally avoided playing in the cell therapy space so far, so its purchase of Gracell reflects a belief that cell therapy has turned a corner and that new manufacturing approaches—alongside other “structural” improvements—can finally help CAR-Ts go more mainstream.

Transition to the Outpatient Setting

Better manufacturing is only part of the story. While that may help on the supply side, it will need to be supported by further improvements to relieve hospital pressures. One of the big enablers for taking CAR-Ts mainstream would be to move delivery to the outpatient setting.

Some of the key drivers of this effort are current reimbursement structures, which make inpatient administration of these therapies undesirable. Plus, outpatient administration may help reduce the negative impact on hospital bed capacity. The safe extension of care into the outpatient setting can increase the number of patients a treatment center can manage with existing resources.

Already, some hospitals are making investments in building outpatient centers. To offer one example, Marcel van den Brink, MD, PhD and President of City of Hope Los Angeles and National Medical Center said, “In Los Angeles, we plan to complete the construction of our brand-new outpatient center in 2024. As health care advances, more of our cancer care — even complex, innovative care like CAR-T cell therapy — can be done in an outpatient setting. This eight-story, 350,000-square-foot facility is part of a $1 billion investment in our comprehensive cancer center campus and will double the number of exam rooms and infusion capacity in the outpatient setting.”

In 2024, we expect a steady stream of data from CAR-T players on how it can be successfully and cost-effectively delivered in the outpatient setting, as well as data on prophylactic approaches to reduce the side effect burden. We think 2024 is a key year for CAR-Ts to push their market expansion. In 2025, we expect the bi-specifics, their key competitors, to make more of an explicit head-to-head argument for utilization in earlier lines of therapy, and potentially before CAR-T approaches.

Point-of-Care CAR-Ts

Finally, point-of-care CAR-Ts are likely to continue generating some buzz. In Spain, a hospital has started manufacturing CAR-T within the clinic under a special European policy. The CAR-T, developed by the hospital’s experts, has won regulatory approval in Spain and is reimbursed by the national health system like other authorized medications.

There was also some buzz around point-of-care CAR-Ts, wherein there exists the “potential for administration of a fresh product, a median vein-to-vein time of 7 days (i.e. the time between T-cell collection and CAR-T infusion), and greater physician oversight throughout the process.” However, we generally expect the impact in the US to be low.

Radiopharmaceuticals will grow further, with expanded emphasis on alpha emitters.

2023 was the year of radiopharmaceuticals.  We expect that trend to continue throughout 2024, with high levels of activity.  We also think companies will try to pivot to alpha emitters.

In comparison to beta emitters (177Lu or 131I), which produce beta particles and cause mostly single stranded DNA breaks, alpha emitters (such as 225Ac and 223Ra) can produce double-stranded DNA breaks and can cause much more damage to cancerous tissue. The hope is that this can further improve the efficacy seen with radiopharmaceuticals.

Since alpha particles travel only a short distance, they can more effectively localize the radiation to the tumor. Their limited penetration range reduces the risk of damage to surrounding healthy tissues, improving the therapeutic index and reducing side effects.

There are multiple alpha emitter trials being run by pharmaceutical companies that can potentially read out in 2024. Here’s an overview:

  • Fusion Pharma: 3 active trials (NCT03746431, NCT05605522, NCT05219500) in early stage targeting solid tumors and metastatic castration-resistant prostate cancer (mCRPC)
  • Bayer: Phase 1 (NCT04147819) targeting HER2-expressing tumors that failed to respond to standard therapies
  • AdvanCell: Evaluating a phase 1 / 2 study (NCT05720130) in patients with PSMA-positive mCRPC
  • Novartis: Conducting a phase 1 trial (NCT04597411) in patients with PSMA-positive PC
  • Janssen: Conducting a phase 1 trial (NCT04644770) in patients with mCRPC with prior androgen receptor pathway inhibitor (ARPI) exposure
  • Radiomedix and Orano Med: Both the companies are collaborating on two early-stage studies (NCT03466216), (NCT05153772) among patients with unresectable metastatic neuroendocrine tumors
  • RayzeBio (Acquired by BMS): Conducting two studies (NCT05477576), (NCT05595460) targeting gastropancreatic tumors and extensive stage NSCLC
  • Orano Med: Apart from the collaboration, evaluating a phase 1 study (NCT05283330) among patients with recurrent or metastatic gastrin-releasing peptide receptor (GRPR)-expressing tumors
  • Actinium Pharma: Conducting four early-stage studies (NCT02575963), (NCT03441048), (NCT03867682), (NCT03932318), all focused on hematological malignancies

Promising data from the trials in progress could help the field grow beyond the few targets it is currently restricted to, and into other tumor types.

Another indicator of the rapidly growing interest in alpha emitters is that market leaders with “first-generation” beta emitters are now developing their own alpha emitter follow-on programs. Lilly / Point Biopharma’s PNT2001 is being tested in PSMA-positive mCRPC. It uses actinium-225 (an alpha emitter) as the radioisotope. “That’s significant as Point’s lead, PNT2002, is a lutetium-177-containing anti-PSMA, so advancing PNT2001 sees Lilly expanding Point’s work into alpha emitters.”

Interestingly alpha emitters are also being evaluated as sequencing options after beta emitters. For example, Fusion’s lead program, FPI-2265, is evaluating 225Ac-PSMA I&T, a small molecule targeting PSMA expressed in prostate cancers. The alpha-emitting radiopharmaceutical is being evaluated in the Phase 2 TATCIST trial. The TATCIST trial is designed to evaluate patients with mCRPC with progressive disease, including patients who are naïve to PSMA-targeted radiopharmaceuticals and those who have been pre-treated with 177Lu-based PSMA radiopharmaceuticals such as PLUVICTO®.

Finally, we expect business development activity to continue.  “FOMO” or the “fear of missing out” is a healthy motivator, and we think it will lead other large biopharma companies to get involved. With Lilly and BMS jumping into the mix late last year, we expect the business development floodgates to open with a number of big pharma companies committing to the space either through partnerships or acquisitions.

Targeted protein degradation will finally “arrive.”

Targeted protein degradation (TPD) has quietly matured over the past few years.  As a brief introduction, with TPD, researchers harness the cell’s own protein degradation machinery in an attempt to eradicate disease-causing proteins. The technology’s promise is that several classes of proteins that were previously considered “undruggable” could now be drugged.

We (and others) believe that 2024 will be a transformative year for TPD. This year, we expect the first phase 3 trial to read out in this space (see below). In addition, we expect several TPD agents to enter pivotal trials, as well as to see more promising data from other early programs.

Our enthusiasm stems from several recent data releases that show TPD’s promise.  For starters, late last year Arvinas and Pfizer announced interim data from a phase 1b trial of vepdegestrant in combination with palbociclib (IBRANCE®).  It showed an impressive overall response rate (ORR) of 42% and median progression-free survival of 11.1 months in heavily pre-treated patients (after 11 months median follow-up time).  Importantly, tolerability is generally consistent with that of palbociclib and what has been observed in other clinical trials of vepdegestrant. Vepdegestrant is already in a phase 3 study, and data are expected this year. If successful, we expect it to be approved and to serve as a catalyst for further investment in this area.

Several earlier stage programs have also showed promising data:

  • NX-2127, a BTK-targeted protein degrader, was tested in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and B-Cell malignancies. This first-in-human trial demonstrated proof of efficacy, and the data supports further clinical development of NX-2127 in CLL.
  • Kymera Therapeutics presented interim results from its STAT3 degrader (KT-333) phase 1 trial at ASH in 2023. It demonstrated early signs of antitumor activity across liquid and solid tumors, including major responses in cutaneous T-cell lymphoma (CTCL) and Hodgkin’s lymphoma.  It showed robust STAT3 knockdown and positive immunomodulatory effects. It also appeared to be well-tolerated with a good safety profile.
  • C4 Therapeutics announced positive data for its TPD asset, CFT7455. In the phase 1 trial in relapsed/refractory multiple myeloma (MM), it demonstrated promising signs of anti-myeloma and immunomodulatory activity when combined with dexamethasone, particularly in patients who have undergone numerous lines of prior therapy for MM, including BCMA therapies.  It also seemed well-tolerated.

All those results seem to indicate a bright future for TPD.  Overall, 2024 holds a lot of promise in the broader oncology market, as progress continues in multiple areas that we’ve monitored for some time.  As the year progresses, we’ll be watching, and we’ll be sure to write or comment on any new developments that could have an impact.  Be sure to check our blog and Resource Center regularly.  Alternatively, follow us on LinkedIn and see everything we publish.