By Chris Biondi, Ned Wydysh, Vivek Mittal, Earl Gillespie, Steven Chang, Heather Loring, and Justyna Bomba
Given the dire nature of cancer, it comes as no surprise that this therapeutic area saw the first approvals of novel classes of targeted and cell therapies. The first targeted therapy was approved ~30 years ago in breast cancer while ~5 years ago we saw the first approval of an autologous cell therapy for hematologic malignancies. Approvals and late-stage data releases in the past year or so have demonstrated a maturation of these biologic modalities and strategies. Three key themes underlying this maturation are apparent:
- B-cell malignancies remain an attractive yet increasingly competitive proving ground for biologics
- Melanoma continues to be a proving ground for novel IO approaches
- There is continued penetrance of precision medicine into more niche oncology indications
B-cell Malignancies Remain an Attractive Yet Increasingly Competitive Proving Ground for Biologics
Novel biologics like cell therapies and bispecifics are overrepresented in B-cell malignancies. In these indications, these types of assets represent ~30% of the pipeline today. But from an epidemiological perspective, B-cell malignancies only comprise ~10% of all US cancer diagnoses (Figure 1). Development efforts of these types of biologics in B-cell malignancies have even accelerated compared to all other cancer indications. Cell therapy and bispecific assets in B-cell malignancies have grown at a ~20% 10-year CAGR as opposed to the ~10% 10-year CAGR they have experienced in all other cancer indications (Figure 2). Several factors have contributed to the rise of biologic modalities in B-cell malignancies. B-cells are not crucial for survival and CD19, CD20, and BCMA are only expressed on these cell types, creating remarkably “clean” targets. Hematologic malignancies as a whole are far easier for biologics-based therapies to engage the tumor target, whereas in solid tumors, malignant tissue can be occluded by the immunosuppressive tumor microenvironment. For new modalities like bispecifics and CAR-Ts, the ability to effectively target cancer cells while minimizing toxicity creates an attractive proving ground on a mechanistic basis.
Recent and upcoming approvals will continue to build on this trend, with T-cell engaging bispecifics serving as an interesting example. This year, Tecvayli was the first FDA approved bispecific BCMA directed CD3 T-cell engager in multiple myeloma. Epcoritamab, glofitamab, odronextamab, and mosunetuzumab are CD20 directed T-cell engagers expected to be approved by the FDA in the near future. Furthermore, the attractive safety profiles of drugs like mosunetuzumab are likely to support physician uptake and use in outpatient settings.
B-cell malignancies will also serve as a proving ground for CAR-T therapies pursuing targets outside of CD19. The approval of Carvykti (BCMA directed autologous CAR-T) on the heels of Abecma’s approval (2021), demonstrates how this therapeutic area is most likely to see innovations in this modality.
Naturally, the proliferation of these therapies has in kind created a highly competitive environment for biologics in these indications. Therapies in development must stack up against the many treatment options available for B-cell malignancies, leading to aggressive trial strategies designed to establish clinical differentiation. As an example, Blenrep (BCMA targeting ADC) was recently withdrawn from the market after failing to demonstrate improvement over dexamethasone + pomalidomide in multiple myeloma.
While B-cell malignancies are attractive for technological innovations in biologics, savvy drug developers must also keep in mind the competitive nature of the space.
Melanoma Continues to be a Starting Point for Novel IO Approaches
Melanoma has long been a focus of immuno-oncology (IO) drug development efforts. Paradigm-shifting treatments targeting CTLA-4 and PD(L)1 were first approved for advanced patients with this disease in the early 2010’s. These efforts even reach back to 1998, when the FDA approved IL-2 as an “immunotherapeutic treatment” for metastatic melanoma.
For several reasons, melanoma remains a starting point for many novel IO approaches. The combination of high concentrations of immune cell infiltrates, inability of many patients to achieve meaningful responses, and relatively high prevalence, provides a salient rationale for focusing on these patients. This year, there were several therapies and data releases in melanoma taking cutting-edge approaches to IO. The most exciting examples being KIMMTRAK, Opdualag, Lifileucel, and mRNA-4157/V940.
- KIMMTRAK (Approved, metastatic uveal melanoma): The only T-cell engaging bispecific to target a specific, HLA allele (HLA-A*02:01)
- Opdualag (Approved, unresectable or metastatic melanoma): The first LAG-3 (lymphocyte activation gene-3) inhibitor, relatlimab, approved in combination with nivolumab (anti-PD1)
- Lifileucel (Expedited Review Designation, unresectable or metastatic melanoma): potential to be the first-to-market tumor-infiltrating lymphocyte (TIL) therapy
- mRNA-4157/V940 (Phase 2b, advanced melanoma): The first demonstration of clinical efficacy of a personalized cancer vaccine in a randomized controlled trial, demonstrating reduced risk of recurrence or death by 44% compared to Keytruda alone.
Although there are certainly interesting IO developments in other indications, novel IO approaches are likely to continue emerging in melanoma. Immunotherapies targeting GITR (TNF superfamily 18) and TIGIT (T-cell immunoreceptor with IG and ITIM domains) are in clinical development in this indication. Assets pursuing these targets are also in late-stage development in other solid tumor indications, such as NSCLC, indicating that these novel IO approaches may be on the horizon for broader populations of patients.
Continued Penetrance of Precision Medicine into More Niche Indications
Precision medicine approaches relegated to select oncology indications are now penetrating less-served patient populations. In the past year or so, there have been many approvals and late-stage data readouts that demonstrated better outcomes through the targeting of patients’ underlying disease drivers (Figure 3). At a high level, these innovations can be categorized as “Iterations” and “Expansions”. Iterations represent improvements on existing targeting strategies where there are validated targets and proved modalities at the indication level. Expansions leverage these same precision medicine approaches but apply them to indications where those strategies are not established. While numerous assets fall under both categories, the most representative examples of each are Pluvicto and Lytgobi for iterations and Enhertu and tucatinib + trastuzumab for expansions.
Pluvicto is a newly approved radiotherapy that targets PSMA. PSMA has long been targeted by labeled antibodies for imaging purposes in prostate cancer. Pluvicto is an iteration of targeting this antigen that offers the first anti-cancer approach. Lytgobi targets FGFR2 mutants in cholangiocarcinoma. Although FGFR inhibitors exist, this therapy inhibits the target through covalent binding, as opposed to the reversible ATP competitive binding of existing drugs.
Enhertu and tucatinib + trastuzumab target HER2. HER pathway targeting has been used in breast cancer for nearly 30 years but is seeing its first forays into the small subsets of HER2 mutants in NSCLC and CRC. Both Enhertu and tucatinib + trastuzumab are the first of their kind to target this pathway in these indications.
To say all exciting data releases and approvals this year neatly fall within these categories would be unduly prescriptive. There are some exceptions worth noting that still indicate precision medicine is reaching more niche populations. Elahare, for example, is the first folate receptor alpha targeted therapy for ovarian cancer, approved alongside a companion diagnostic. Nonetheless, this year demonstrated an increased penetration of precision medicine and meaningful benefits to broad swaths of underserved patients.
Implications for the Future
This year has shown us that trends in oncology over the last few years are continuing, or more aptly, maturing. Drug developers are still pursuing proof-of-concept in “simpler” indications and precision medicine is still realizing better results than “all-comer” approaches. The best positioned biopharma players will consider how to adapt and win in the face of these enduring dynamics.
In indications like B-cell malignancies, there will always be intense competition for novel biologics. But value can still be built as long as the strategic goals are clear: is this an opportunity to de-risk the technology or a true plan for commercial growth? Immuno-oncology, regardless of indication, will no doubt create challenges for designing a strategy that reflects the future standard-of-care. In more niche indications with gaps in precision medicine approaches, it is essential to consider a diagnostics strategy that can maximize program value.
Health Advances’ expertise in oncology and precision medicine uniquely positions us to work closely with companies to understand the ever-evolving oncology landscape and optimize their commercial or development strategies.
Chris Biondi is a Consultant and member of the Biopharma practice at Health Advances. Prior to joining Health Advances, Chris completed his MBA at Northwestern University and was a scientist at Pfizer Oncology.
Vivek Mittal is a Partner and Managing Director at Health Advances. He leads the San Francisco office and is focused on building Health Advances expertise in translational medicine through his work across therapeutics, diagnostics, and life science tools. Prior to Health Advances, he earned his PhD in Molecular Biology at Washington University in Saint Louis.
Ned Wydysh is a Vice President at Health Advances and a leader of the Biopharma practice. He is co-leader of the Cell and Gene Therapy practice and a leader of the Oncology Business Development Committee. He received his PhD in Chemistry from Johns Hopkins University.
Earl Gillespie is a Senior Director and a member of the Biopharma practice at Health Advances. He earned his PhD in Pharmacology and Experimental Therapeutics at Boston University School of Medicine.
Steven Chang is an Engagement Manager and a member of the Biopharma practice at Health Advances. Steven received his PhD in Biological Engineering from MIT prior to Health Advances.
Heather Loring is a Senior Analyst and a member of the Biopharma and Precision Medicine practices at Health Advances. Prior to joining Health Advances, Heather received her PhD in Biochemistry and Molecular Pharmacology from UMass Medical School.
Justyna Bomba is a Consultant and a member of the Biopharma and Precision Medicine practices at Health Advances. She represents the Swiss office of Health Advances and has an extensive expertise in the European markets.