Stopping cancer in its tracks with new approaches in oncology

By Susan Galbraith, MD, PhD; Executive Vice President, Oncology Research & Development, AstraZeneca

Since I first started training as an oncologist nearly 30 years ago as an eager young scientist, there has been phenomenal progress made toward finding cures for cancer in every form. And now, leading Oncology R&D at AstraZeneca, I am inspired every day by the researchers whose work makes this progress possible and the cutting-edge science they are driving to develop the next wave of cancer therapies.

We’re rapidly gaining a deeper understanding of the wealth of potential drug targets to address human disease. These targets go beyond traditional small molecules, monoclonal antibodies, and peptides, and may hold the keys to unlock new treatments and potential cures. At AstraZeneca, we are using a multi-pronged approach — broadening therapeutic targets and investing in genomic data, next-generation sequencing, and CRISPR gene editing — to identify, interrogate, and validate new targets in a way not previously thought possible.

With this in mind we approach developing transformational medicines in two distinct ways:

• Targeting cancer cell drivers and treatment resistance to stop cancer cells in their tracks
• Activating the immune system to bring us closer to a cure potentially

This strategy allows us to better understand and attack cancer from every angle, from identifying different causes to creating novel treatment combinations that have the potential to improve patient outcomes. Through this relentless quest for innovation, we have created one of the most diverse portfolios in the industry to tackle cancers with the greatest unmet need.

Developing new medicines that target cancer cell drivers and overcome resistance

Antibody drug conjugates (ADCs) are exceptional cancer-killing agents that could become the new backbone in treatment combinations. Unlike conventional chemotherapy treatments, ADCs deliver a drug directly into cancer cells and limit damage to healthy ones.ⁱ We are investigating ADCs to target oncogenes, like HER2, and promising molecular targets in solid tumors like TROP2. In some of the hardest-to-treat tumor types, like triple-negative breast cancer, we’re also exploring the power of combining ADCs and immunotherapy. The potential of ADCs to improve the treatment of breast, lung, gastric and other cancers is tremendous, and we’re bringing forward the next wave of these treatments to potentially replace chemotherapy and radiotherapy.

We can also now create medicines that exploit the body’s multiple ways of detecting and repairing DNA damage, known as DNA Damage Response (DDR) mechanisms. Many cancers have lost one of these DDR mechanisms, which make them vulnerable to targeting other parts of these pathways.ⁱⁱ Cancer cells also have incredibly high mutation rates, which results in dysfunctional cellular machinery and damaged DNA. While these cells can survive with a certain level of damage, there is a limit. Our goal is to develop innovative, targeted, and biomarker-driven treatments that exploit these vulnerabilities — and we are leaders in this field. In 2014, AstraZeneca drove approval of the first PARP inhibitorⁱⁱⁱ, and we are building on this success by developing DDR medicines with the potential to maximize DNA damage to, and selectively kill, cancer cells.

Many patients who initially respond to such targeted therapies develop resistance to their treatment, causing it to stop working on cancer cells.^iv That’s why we’re zeroing in on how to target the genetic mutations and resistance mechanisms that allow this. New treatments and combinations in a range of resistant cancers, including non-small cell lung cancer (NSCLC), and targeting multiple biological pathways simultaneously, such as EGFR mutations and MET gene alterations, can potentially extend survival for patients.^v

However, not all cancers are driven by direct changes to the genome. The patterns of how different genes are expressed or repressed in different settings — called epigenetics — can also lead to cancer and to drug resistance.^vi We’re launching several projects to better understand epigenetics and to uncover new mechanisms and therapies that combat these disruptions.

Aiming for a cure by activating the immune system

In addition to targeting mutations and epigenetic changes in cancer, we are also leading immuno-oncology (IO) research to open the door to much-needed immunotherapies. IO therapies can spur recognition of the presence of cancer that the human body’s own immune surveillance mechanisms may have missed, and can overcome the immunosuppressive mechanisms that cancers frequently develop as they evolve.^vii,viii These options have become the established backbone of many cancer regimens.

Our broad pipeline features a range of potential first-in-class IO therapies across multiple tumor types — with promise across all stages of disease, and lines of therapy. In 2021, we are excited to see updates from numerous innovative clinical trials — including promising data in NSCLC — where we are exploring novel combinations of IO drugs to extend efficacy potential to patients with unmet needs.^ix,x

We also see promising results, beyond activating the overall immune system, by activating existing T-cells through immune engagers. So far this approach has been applied to blood cancers.^xi But we don’t want to stop there, as we believe these therapies have the potential to improve patient outcomes in hard-to-treat solid tumors. 

AstraZeneca is also exploring the potential of cell therapies to amplify the body’s natural immune response to recognize and attack tumor cells. We are investing significantly in this field with eight assets addressing major tumors currently in development, which we believe can put cures within reach one day. We are also looking for new ways to enhance cell therapy through combinations with other agents in our portfolio and via strategic research collaborations.

However, we still need to identify and treat disease earlier for optimal outcomes in cancer with these new molecules, targets, and combinations. We are looking to detect cancer signals sooner with our early adoption of circulating tumor DNA (ctDNA) testing to identify patients most at risk of their cancer returning^xii-xvii — and where earlier treatment intervention could have a profound benefit.

When I think back to my early days in the clinic and the lab, and see how far we’ve come, I’m genuinely proud of the strides we’re making and the impact of pioneering research discoveries in the lives of patients. We are unraveling the complexities of some of the most hostile and hard-to-treat cancers, generating better outcomes for patients, and fearlessly paving the way to a revolution in cancer treatment. This innovation is directly reflected in our increasingly diverse pipeline and portfolio, and in the brilliant people I have the privilege to work with every day.

We are on the cusp of significant advances in the way we treat cancer and bringing more transformative medicines to patients through the many approaches I’ve described. By following the science, being bold, and not fearing failure, we are getting closer to our mission of offering a potential for cure for an increasing proportion of the millions of people worldwide living with cancer.

For more information, visit astrazeneca.com.

ⁱ Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225. Accessed September 2021.
ⁱⁱ Hakem R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 2008;27(4):589-605. Accessed September 2021.
ⁱⁱⁱ Mullard A. European regulators approve first PARP inhibitor. Nat Rev Drug Discov. 2014;13:877. Accessed September 2021.
^iv Ellis LM, Hicklin DJ. Resistance to targeted therapies: Refining anticancer therapy in the era of molecular Oncology. Clin Cancer Res. 2009;15(24):7471-7478. Accessed September 2021.
^v Sequist L, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. The Lancet Onc. 2020;21(3):373-386. Accessed September 2021.
^vi Baylin SB, Jones PA. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016; 8(9): a019505. Accessed September 2021.
^vii Melero I, et al. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19(5):997-1008. Accessed September 2021.
^viii Cancer Research UK. The immune system and cancer. Available online. Accessed September 2021.
^ix Johnson ML. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for NSCLC: Results from the phase 3 POSEIDON study [presentation]. Presented at: IASLC 2021 World conference on Lung Cancer; September 8-14, 2021 (Virtual Meeting).
^x Martinez-Marti A. COAST: an open-label, randomised, phase 2 platform study of durvalumab alone or in combination with novel agents in patients with locally advanced, unresectable, Stage III NSCLC [presentation]. Presented at: The ESMO Congress 2021; September 16-21, 2021 (Virtual Meeting).
^xi Zhou S, et al. The landscape of bispecific T cell engager in cancer treatment. Biomark Res. 2021;9(38). Accessed September 2021.
^xii Zhang Q, et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Dis. 2020; (12)10: 1842. Accessed September 2021.
^xiii Gray JE, et al. Tissue and plasma EGFR mutation analysis in the FLAURA trail: Osimertinib vs comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR mutated advanced non-small cell lung cancer. Clinical Cancer Res. 2019;1126. Accessed September 2021.
^xiv Garcia-Murilla I, et al. Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol. 2019;5(10):1473-1478. Accessed September 2021.
^xv Raja R, et al. Early reduction in ctDNA predicts survival in patients with lung and bladder cancer treated with durvalumab. Clin Cancer Res. 2018; 24(24):6212-6222. Accessed September 2021.
^xvi Peters S et al. MERMAID-01: A phase III study of adjuvant durvalumab plus chemotherapy in resected NSCLC patient with MRD+ post-surgery. JTO. 2021; 16(3). Accessed September 2021.
^xvii Spigel DR et al. MERMAID-02: Phase III study of durvalumab in patients with resected, stage II-III NSCLC who become MRD+ after curative-intent therapy. JTO. 2021; 16(4). Accessed September 2021.

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