Cancer and the Role of Small Molecules

The oncology field continues to evolve as drug developers gain a better understanding of oncogenic driver mutations. Data show improvements in overall cancer survival over the last 10 years – with survival doubling from 24 percent to 50 percent in the UK alone. Lung cancer patients have also seen a slight increase in survival rates over the same period.

Many of the advances in treatment are thanks to small molecules. Small molecule targeted agents still make up the lion’s share of treatment options, but there is room for the efficacy and safety of treatments to improve. Although we recognize the benefit of small molecules and believe that small molecule drugs have the potential to reach more cancer patients, we must remain committed to developing further targeted therapies, and open to other modalities.

Many players in the small molecules space are working to foster partnerships with the aim of developing best-in-class agents; others aim to treat patients with untargeted driver mutations. Treatment options for cancer patients are no longer based on the histological origin of the cancer alone (i.e. pancreatic cancer, lung cancer, breast cancer); cancers are now also treated based on their genetic profiling, enabling the identification of specific driving genetic mutations at the origin of the abnormal cell proliferation. This has led to the development of many inhibitors specifically addressing these mutations, with small molecules and antibodies being the most prominent modalities.

However, some genetic alterations have been particularly difficult to target – very much like failing to find the right key for a given lock. Moreover, drug-related cancer resistance is a major issue: new mutations arise and allow some cancer cells to escape from targeted agent efficacy. Companies focusing on developing new targeted agents to address new cancer subtypes (i.e. cancers with newly identified genetic alterations) or resistance mechanisms could offer new treatment options to cancer patients and ultimately improve patient outcomes.

Addressing mechanisms of resistance at the single mutation point with high-resolution genetic analysis data is a good place to start. High-resolution genetic sequencing and structural analysis of mutant proteins have revolutionized the development of targeted therapies by enabling precise characterization of the conformation of mutant proteins to allow structure-based drug design. One concrete example of new targets recently approved include KRAS G12C inhibitors, such as Lumakras (sotorasib) or Krazati (adagrasib). KRAS was previously considered an undruggable target, but progress in high-resolution protein characterization has fostered the development of new small molecules that are able to target specific mutants (e.g., the mutant form G12C). Other examples include NTRK, RET, PIK3CA, and IDH1/2. The precise characterization of newly acquired genetic mutations at the origin of drug-related resistance mechanisms became another possibility to support the development of new inhibitors.

Examples in EGFR-mutated lung cancers
 

First- and second-generation epidermal growth factor inhibitors (EGFRi) such as erlotinib, gefitinib, and afatinib led to EGFR T790M mutations that can now be targeted by a third generation EGFRi, osimertinib. However, osimertinib will ultimately lead to C797S mutations.

At Pierre Fabre Laboratories, we are currently developing a fourth generation EGFRi (PFL-241) specifically designed to target C797S mutations post-osimertinib treatment.

Our other contributions to cancer treatment included BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib), which was granted European marketing authorization in September 2018 for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF^V600 mutation. It’s a good example of innovation within the BRAF class. During its development, encorafenib showed specific PK and PD preclinical properties compared to other marketed BRAF inhibitors. These differences could translate into a differentiated efficacy and safety profile particularly relevant for melanoma patients. Hence, why clinical development was pursued.

Despite being the third such treatment to the market, encorafenib, in combination with binimetinib, is now the market leader for melanoma treatment in Europe, highlighting that first-in class is no longer the only success factor for drug developers.

We are also developing a novel RAS/RAF targeted agent (exarafenib) to expand its ability to treat patients beyond BRAF^V600 mutations, and recently introduced a new formulation of MEKTOVI (45mg) to reduce pill intake from three to one and making improvements in manufacturing and supply chain processes. The mission is now to ensure that the approval of BRAFTOVI in combination with MEKTOVI for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF^v600E mutation translates rapidly in patient access. The vision is to revolutionize cancer care alongside our partners, healthcare professionals, and patient groups. I believe in providing the right treatment for the right patient at the right time, and putting the needs of patients at the heart of the business strategy.

As part of the overall oncology community, small molecule manufacturers are striving to address the critical needs in cancer care by committing to the delivery of clinically meaningful treatments, adapting to contemporary needs, and learning a little more about what works at every stage of the process. Every time we care for a single patient, we make the whole world better.

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