From Blunt Instruments to Molecular Precision: 40 Years of Oncology Evolution

The past 4 decades of oncology resemble a twisted, evolving road, starting with cytotoxic foundations and ending with our current landmark of molecular mastery in cancer treatment.

In 1986, the oncologic tool kit was rudimentary, defined by “blunt instrument” chemotherapies that targeted cell division rather than cell identity, and lacked clear strategies for managing severe treatment-related adverse effects.

Today, we have entered the era of precision selectivity, explained Julie Gralow, MD, who serves as chief medical officer and executive vice president of the American Society of Clinical Oncology (ASCO), in an interview with ONCOLOGY.

“Instead of just chemotherapy that targets all rapidly dividing cells, we have become much more targeted and much more elegant,” Gralow said. “We’ve moved from monoclonal antibodies to combination strategies, and now to antibody-drug conjugates [ADCs] and bispecifics—it is thrilling to see that evolution.”

In this wide-ranging discussion, Gralow, who previously was the director of breast medical oncology at Fred Hutch Cancer Center, traces the lineage of this revolution, from the early days of tamoxifen to the modern “cool factor” of bispecific antibodies and chimeric antigen receptor (CAR) T-cell products, as well as the breakthrough of the bystander effect in ADCs.

The Dawn of Targeting

Gralow highlighted the state of cancer therapy from her early training days, when tamoxifen, identified as a selective estrogen receptor modulator, was the lone targeted outlier in a world of cytotoxic chemotherapy. Its long-term use in the adjuvant setting has been a game changer for patients with breast cancer and has a favorable risk-benefit ratio in high-risk premenopausal women.¹

But then came the groundbreaking milestone with the HER2 target, specifically also in breast cancer, in which the 1998 FDA approval of trastuzumab (Herceptin)² was a pivotal moment that shifted the oncology mindset, she said.

“Depending on how you view tamoxifen, this was the beginning of targeting subsets of breast cancer,” Gralow said.

Targeting HER2 opened the door to a multitude of gene therapies and their accompanying molecular testing for patients upon receiving their diagnosis. If a patient is harboring an actionable mutation, it has become more common than not that the next step is to determine what appropriate targeted treatments exist and in what line of therapy the patient should receive them.

“I’ve watched that progression move from monoclonal antibodies to combination strategies, small molecules, and then to [ADCs],” Gralow said. “Now, we have HER2-targeted bispecific antibodies, which is amazingly cool. We just saw a presentation on zanidatamab-hrii [Ziihera] in gastroesophageal [GEJ] cancer at the 2026 ASCO [gastrointestinal cancer] meeting. It is thrilling to see how we’ve taken our knowledge of HER2 as a gene and used it to develop highly effective therapies that have markedly changed patient outcomes.”

A handful of bispecific antibodies, which are engineered antibodies designed to simultaneously bind to 2 different antigens or epitopes that thereby unite 2 different types of cells or block 2 signaling pathways simultaneously, are approved by the FDA:

• Zanidatamab: This HER2-targeting bispecific antibody is approved for advanced biliary tract cancers and is being evaluated in phase 3 trials for HER2-positive gastric and GEJ cancers.
• Teclistamab-cqyv (Tecvayli): Targets BCMA on multiple myeloma cells and CD3 on T cells. It is approved for relapsed/refractory multiple myeloma.
• Talquetamab-tgvs (Talvey): Targets GPRC5D on multiple myeloma cells and CD3 on T cells. It is also approved for relapsed/refractory multiple myeloma.
• Elranatamab-bcmm (Elrexfio): Another BCMA x CD3 bispecific antibody, approved for relapsed/refractory multiple myeloma.
• Amivantamab-vmjw (Rybrevant): Targets EGFR and MET. It is approved for non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations.
• Zenocutuzumab-zbco (Bizengri): Targets HER2 and HER3, blocking HER2-HER3 dimerization and NRG1 fusion protein interactions. It is approved for NRG1 fusion-positive cancers, including some NSCLCs.

The ADC and Cellular Revolution

Another shift that came from the monoclonal antibody approach is that of ADCs and their well-known bystander effect. Such ADCs include ado-trastuzumab emtansine (Kadcyla; T-DM1) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), which have made inroads in the breast cancer pipeline. T-DXd has recharged the paradigms of both lung and gastric cancers as well. Others that have made it to market include gemtuzumab ozogamicin (Mylotarg), brentuximab vedotin (Adcetris), inotuzumab ozogamicin (Besponsa), polatuzumab vedotin-piiq (Polivy), enfortumab vedotin (Padcev), and sacituzumab govitecan (Trodelvy), to name a few.

“We’re still learning how ADCs work,” Gralow emphasized. “A key recent development is the understanding that you don’t need much of the target on the cancer cells for these drugs to work. In the past, traditional HER2 antibodies and small molecules didn’t work unless HER2 was overexpressed. Now, with ADCs, you can have minimal expression, bring the molecule in, and then cleave it to release the antibody.”

Many, though not all, ADCs are also known to have a bystander effect, in which once the cytotoxic drug is released within the targeted cancer cell, it can diffuse outside of it and initiate cell death in nearby cells; this includes those that do not express the tumor antigen and enhances the overall antitumor ADC activity.

“With the bystander effect, the drug can seep back out so that even if all the cancer cells don’t have the target, those in the vicinity will be impacted,” Gralow explained. “With T-DXd, we’ve learned you can have very low levels of HER2 and still get benefit. This has forced our pathologists to go back to the drawing board to distinguish between ‘true’ [ultralow] and HER2 low [1+].”

T-DXd, for example, is indicated for patients with unresectable or metastatic HER2-low or HER2-ultralow breast cancer who have been previously treated with at least 1 type of endocrine therapy in the metastatic setting.³

The Management Challenge

One would be remiss to highlight the progress of anticancer therapies over the past 4 decades without mentioning immunotherapy, specifically immune checkpoint inhibitors. Starting in 2011 with the approval of ipilimumab (Yervoy)—a CTLA-4 inhibitor, which marked the first approval for this class of agents—a wave of PD-1/PD-L1–directed therapies followed over the years and across multiple disease states⁴:

• Ipilimumab: Metastatic microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) colorectal cancer (CRC), melanoma, advanced clear cell renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and NSCLC.
• Pembrolizumab (Keytruda): Urothelial carcinoma, select gastric and GEJ, HER2-negative gastric or GEJ adenocarcinoma, locally advanced or metastatic esophageal/GEJ carcinoma, NSCLC, RCC, melanoma, malignant pleural mesothelioma (MPM), head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, MSI-H/dMMR cancer, metastatic MSI-H/dMMR CRC, cervical cancer, HCC, biliary tract cancer (BTC), Merkel cell carcinoma, endometrial cancer, tumor mutational burden–high cancer, cutaneous squamous cell carcinoma, and triple-negative breast cancer.
• Nivolumab (Opdivo): Melanoma, NSCLC, MPM, RCC, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, CRC, HCC, esophageal cancer, gastric/GEJ cancer.
• Durvalumab (Imfinzi): NSCLC, small cell lung cancer (SCLC), BTC, HCC, dMMR endometrial cancer, muscle invasive bladder cancer (MIBC), and gastric/GEJ adenocarcinoma.
• Atezolizumab (Tecentriq): NSCLC, SCLC, HCC, and melanoma.
• Tremelimumab (Imjudo): NSCLC, SCLC, gastric/GEJ adenocarcinoma, HCC, bile duct cancer, gallbladder cancer, MIBC, dMMR endometrial cancer.
• Avelumab (Bavencio): Merkel cell carcinoma, urothelial cancer, and RCC.
• Toripalimab (Loqtorzi): Nasopharyngeal carcinoma.

The idea of using the patient’s own immune system to fight cancer began more than 40 years ago, Gralow emphasized. “One of my first lab exposures as a fellow was looking at tumor vaccines. While we still don’t have an approved tumor vaccine, we have figured out how to manipulate the immune environment. Immune checkpoint inhibitors are effective in most cancers now, but we still have a lot to learn. We have at least a dozen PD-1/PD-L1 inhibitors, and each indication for different cancer types defines the population using a different biomarker. It hasn’t been optimized yet.”

Every drug comes with its own unique toxicity profile, and for immunotherapies, numerous studies since their advent to the landscape have centered on optimal management of their immune-related adverse events, such as pneumonitis, colitis, rashes, and more. ASCO, for example, has a guideline on the management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy.⁵

As part of the guideline, a multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. The development comprised a systematic literature review, with a focus on published evidence from 2017 through 2021, as well as an informal consensus process.

“Our ASCO guideline for immune checkpoint inhibitor toxicity is our most downloaded and accessed guideline,” Gralow said. “As drugs like pembrolizumab go off patent and biosimilars emerge, even low-income settings are figuring out how to manage these drugs safely.”

The guidelines aren’t selective toward checkpoint inhibitors. As CAR T-cell therapies have also trickled into the hematologic cancer pipeline, some of their most common adverse effects require careful management, such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. ASCO published a similar guideline for this class of therapies, also in November 2021.⁶

“With each new class of drug, the key is having the latest information readily accessible. Things are changing so fast that even as a specialist, it’s hard to keep up. We cannot memorize all of this,” Gralow emphasized. “Moving forward, we must use AI [artificial intelligence] to help us access information about the drugs we prescribe and their toxicities.”

She added that ASCO as an organization has a goal of converting every treatment guideline to a “living guideline” in the next year. Most recently, ahead of World Cancer Day, February 4, ASCO published its next living guideline for stage IV NSCLC with driver alterations.⁷ In this version, which offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials, 13 studies were identified in the latest search of the literature to date.

Similarly, for ease of access, ASCO has launched an interactive, AI-powered ASCO Guidelines Assistant, in which ASCO members can utilize an AI-powered tool linked with Google Cloud that navigates through the full guideline library with citations and sources.

“We will use AI to scan the literature for new studies or approvals, but we will still use humans on our panels to provide the perspective: ‘Does this replace the standard?’” Gralow explained.

As more of these novel drug classes come to market, she also shared the outlook on the feasibility of bispecific antibodies vs CAR T-cell therapy for community oncologists. Essentially, where is the guidance—and what is the right approach for the right patient? Safety data will likely play more of a role, especially in the real-world setting.

A systematic review and meta-analysis published in Blood Advances evaluated comparative infection risk in CAR T-cell therapy and bispecific antibodies in patients with B-cell non-Hodgkin lymphoma.⁷ Results showed that of 3202 patients, CAR T-cell therapy and bispecifics had similar rates of all-grade infections per patient (0.44 vs 0.54; P = .18); however, bispecifics demonstrated a higher rate of infection per patient-month at 0.0397 vs 0.0167, respectively (P = .0012).

Similarly, CAR T and bispecifics had similar rates of grade 3 or higher infections per patient at 0.16 vs 0.22, respectively (P = .08). Additionally, bispecifics had a higher rate of grade 3 or higher infections per patient-month (0.0165 vs 0.0069; P = .0003). CAR T-cell and bispecifics products had similar rates of infection-related mortality per patient at 0.04 vs 0.03, respectively (P = .26) and per patient-month (0.0023 vs 0.0022; P = .96).

Safety aside, it’s good to go back to the basics—and truly grapple with the strategy of each treatment approach.

“When I think about cellular therapies, I go back to the Fred Hutch Cancer Center, where [the late] Dr Don Thomas performed the first successful bone marrow transplant in the 1950s. That was a different strategy—giving high doses of chemotherapy to kill the marrow and replacing it with healthy cells,” said Gralow, remembering Thomas, who was a founding faculty member of Fred Hutch and served as the institution’s first medical oncology director.

As oncology knowledge and treatment have shifted toward a more personalized approach dependent on disease characteristics, staging, comorbidities, and more, patient geographic location also plays a role in what is accessible.

“CAR T-cell therapy, first approved in 2017, requires growing cells in a lab and reinfusing them,” Gralow recounted. “For the average community oncologist in a rural area, off-the-shelf bispecifics and allogeneic cells are much more accessible. This [creates] hope in situations where patients are heavily pretreated or have cancers that don’t respond to current standards.”

The Global Mandate

Moving from high-tech labs to rural communities and low-income countries is a hot-button topic in oncology as it relates to equity. A fearless leader in tackling equity issues, Gralow explained how her passion to unite all patients, regardless of whether they live, with these novel therapeutics extends to ASCO, which is a member of the Access to Oncology Medicines (ATOM) Coalition.

The ATOM Coalition, a global initiative led by the Union for International Cancer Control,is working to bridge the gap in cancer care equity. Comprising more than 40 partners across the private and civil society sectors, the coalition targets the systemic barriers preventing the delivery of essential therapies in low- and lower-middle-income countries.

By addressing these hurdles, the ATOM Coalition aims to standardize the quality of oncology care globally, ensuring that a patient’s geography does not dictate their access to lifesaving treatment.

“Whether you survive cancer should not depend on your zip code or where you live,” Gralow said. “We are the educators—providing guidelines and implementation expertise. We’re seeing pilots in Mongolia for breast cancer, with Zambia, Honduras, and Uganda in line. High-quality care must be accessible to everyone, regardless of where they live.”

Global efforts to unite in the fight against cancer continued to be showcased on World Cancer Day 2026, with an international analysis published in Nature Medicine highlighting that approximately 4 of 10 cancer cases in 2022 could have been prevented by avoiding exposure to key preventable risk factors.^9,10

Modifiable risk factors accounted for approximately 7.1 million of the 18.7 million reported cancer cases, representing 37.8% of the total global burden. A significant gender disparity persists in risk-attributable disease: 45.4% of male cancer cases were linked to modifiable factors, compared with 29.7% in female populations.

Additionally, the impact of preventable risks varies significantly by geography:

• Sub-Saharan Africa: Reported the highest burden for women, with 38.2% of cases linked to modifiable risks.
• East Asia: Reported the highest burden for men, with 57.2% of cases associated with these factors.

Primary Drivers of Risk-Attributable Cancer

The data highlight distinct drivers of incidence based on sex, with infections and lifestyle factors playing pivotal roles (Table).

Among women, infections remain the leading modifiable cause of malignancy, whereas tobacco use continues to be the primary driver for men, accounting for nearly one-fourth of all male cancer cases globally. These findings underscore the critical need for gender-specific and region-targeted public health interventions to mitigate global cancer incidence—another core focus of future oncology research.

The Future: 2066 and the End of “Cell of Origin”

In a pipeline that has undergone such a significant transformation across multiple cancer types over 40 years, Gralow has a very particular vision for where future groundwork needs to come from: a world where we treat the mutation, not the organ, and prioritize prevention over treatment.

“I couldn’t have guessed where we would be today 40 years ago, so I’m sure there will be things I can’t even imagine. However, care will become increasingly individualized. We will stop talking about the ‘cell of origin’—is it breast, lung, or colon?—and start talking about the genetic alterations that caused the cancer,” she said, adding that chemotherapy will become less relevant as experts learn to combine targeted therapies and monitor resistance in real time using circulating tumor DNA.

“The biggest improvement in survival will come from preventing cancer in the first place or detecting it very early before it causes problems,” she concluded.

Although the tools have become more elegant, the mission remains the same: individualizing care to the human being behind the diagnosis.

References

1. Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer. 2008;44(1):30-38. doi:10.1016/j.ejca.2007.11.002
2. Kreutzfeldt J, Rozeboom B, Dey N, De P. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res. 2020;10(4):1045-1067.
3. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News release. AstraZeneca. January 27, 2025. Accessed January 27, 2026. https://tinyurl.com/5n8ab8sk
4. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11(1):3801. doi:10.1038/s41467-020-17670-y
5. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440
6. Santomasso BD, Nastoupil LJ, Adkins S, et al. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. J Clin Oncol. 2021;39(35):3978-3992. doi:10.1200/JCO.21.01992
7. Puri S, Leighl NB, Ismaila N, et al. Therapy for stage IV non–small cell lung cancer with driver alterations: ASCO living guideline, 2026.3.0. J Clin Oncol. Published online February 3, 2026. doi:10.1200/JCO-25-02822
8. Access to Oncology Medicines Coalition. Union for International Cancer Control. Accessed February 9, 2026. https://www.uicc.org/atom/atom-coalition-home
9. Fink H, Langselius O, Vignat J, et al. Global and regional cancer burden attributable to modifiable risk factors to inform prevention. Nat Med. Published online February 3, 2026. doi:10.1038/s41591-026-04219-7
10. Four in ten cancer cases could be prevented globally. News release. World Health Organization. February 3, 2026. Accessed February 4, 2026. https://tinyurl.com/3cz7f8an