Lifesaving Upgrades: Reviewing 40 Years of FDA Oncology Approvals

Over the past 40 years, hundreds of drugs have been approved across a multitude of cancer types. With numbers so great, it is guaranteed that some will fall to the wayside and be forgotten while others will persist throughout decades, affecting treatment paradigms even 30 years down the line. In celebration of the journal ONCOLOGY’s 40th anniversary, it was only fitting to document prominent FDA oncology approvals, starting from 1986 and ending in 2026.

June 5, 1986 – Interferon Alfa-2a/2b – Hairy Cell Leukemia

In June 1986, the FDA approved interferon alfa-2a (Roferon-A) and interferon alfa-2b (Intron A) for the treatment of patients 18 years or older with hairy cell leukemia.¹

Claims made in an LA Times article published announcing the approval state that studies using interferon alfa on over 2000 patients demonstrated partial or complete remission in 75% to 90% of patients.

December 18, 1992 – Paclitaxel – Refractory Ovarian Cancer

Paclitaxel, one of the most prominent cancer drugs of all time, was first approved on December 18, 1992, for the treatment of patients with advanced, refractory ovarian cancer.² The agent itself was only discovered when, in the mid-1900s, investigators realized that they needed systemic treatments to destroy cancer cells that had metastasized to different parts of the body. It was in 1962 that a botanist collected bark from the Pacific yew tree and in 1964 when 2 investigators discovered that the extracts were toxic to living cells. The most cytotoxic compound from that tree bark was henceforth dubbed paclitaxel.

Over a decade after its initial discovery, paclitaxel’s antitumor efficacy was confirmed by the National Cancer Institute in mouse models in 1977. Another decade beyond that, in 1989, results from a phase 2 trial evaluating paclitaxel in patients with advanced ovarian cancer were published, demonstrating that 30% of patients responded positively to treatment.² Paclitaxel has since been approved by the FDA for countless other cancer types.

November 26, 1997 – Rituximab – Non-Hodgkin Lymphoma

On November 26, 1997, rituximab (Rituxan) became the first single-agent therapy approved specifically for lymphoma.³ The exact indication was for relapsed/refractory, low-grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma. In the phase 2 IDEC-102 trial (NCT00168740), for which results were published in the Journal of Clinical Oncology in 1998, the overall response rate (ORR) was 48%.⁴

Among 166 patients, for whom the median number of prior therapies was 3 lines, the median duration of response was 11.2 months (range, 1.9-43.1+). Rituximab was administered intravenously at 375 mg/m² weekly for 4 doses. It was reported that most adverse events (AEs) occurred during the first infusion and were frequently grade 1 or 2, including fever and chills. Grade 3 and 4 toxicities occurred in 12% and 3%, respectively.

September 25, 1998 – Trastuzumab – Breast Cancer

On September 25, 1998, the FDA approved trastuzumab (Herceptin) for the treatment of patients with HER2-overexpressing metastatic breast cancer whose tumors have already received at least 1 chemotherapy regimen for metastatic disease.⁵ This approval marked the first by the FDA for a targeted therapy in a solid tumor disease state.

Supporting results for the approval came from a phase 3 trial, of which results were published in the New England Journal of Medicine in March 2001.⁶ Notably, adding trastuzumab to chemotherapy led to a median survival of 25.1 months compared with 20.3 months without trastuzumab (P = .046), which correlated with a 20% reduction in the risk of death. Trastuzumab was also associated with a longer time to disease progression, with a median value of 7.4 months compared with 4.6 months (P < .001).

May 10, 2001 – Imatinib – Chronic Myeloid Leukemia

The FDA approved imatinib (Gleevec) as a treatment for patients with chronic myeloid leukemia (CML); the approval stood for CML in blast crisis (CML-BC), CML in accelerated phase (CML-AP), and CML in chronic phase disease resistant or intolerant to interferon alfa (CML-CP).⁷ Imatinib was the first agent to change CML from a fatal disease to a chronic disease. A report from the FDA highlighted that the approval was based on results from multiple phase 1 and 2 clinical trials.

At the time, among 532 patients with CML-CP, unconfirmed major cytogenetic responses were observed in 49% of patients, complete cytogenetic responses in 30%, and complete hematologic responses in 88%. Among 235 patients with CML-AP, the rate of hematologic response was 63%, with 28% being a complete hematologic response. Among 260 patients with CML-BC, a hematologic response was observed in 26% of patients, with a complete hematologic response in 4%.

The report noted that most patients experienced AEs that were mostly mild to moderate in severity. AEs were found to be more common in patients with advanced disease; however, the investigators noted that they were unsure whether this was due to disease status or the imatinib dose. Edema was also highlighted as the most “troubling” imatinib AE.⁷

February 26, 2004 – Bevacizumab – Metastatic Colorectal Cancer

Bevacizumab (Avastin) was approved in combination with intravenous 5-fluorouracil–based chemotherapy as first-line treatment for patients with metastatic colorectal cancer.⁸ The VEGF inhibitor was the first antiangiogenic therapy approved, targeting the blood vessels that the tumor uses to feed itself as opposed to the tumor itself.

The approval was largely supported by data from the phase 3 AVF2107g trial (NCT00109070), which was published in the New England Journal of Medicine.⁹ Patients were randomly assigned to receive the first-line standard of care at the time, irinotecan, bolus fluorouracil, and leucovorin (IFL), with or without bevacizumab at 5 mg per kg of bodyweight every 2 weeks. The trial showed that the median overall survival (OS) was 15.6 months with IFL, but when adding bevacizumab, it rose to 20.3 months (HR, 0.66; P < .001). Similarly, the median progression-free survival (PFS) rose from 6.2 months to 10.6 months with the addition of bevacizumab (HR, 0.54; P < .001).

The median duration of treatment was 27.6 weeks for the IFL plus placebo group compared with 40.4 weeks for the IFL plus bevacizumab group. Grade 3/4 AEs occurred in 74.0% of the IFL group vs 84.9% when bevacizumab was added to treatment. This increase was mostly attributed to the increase in grade 3 hypertension and small increases in grade 4 diarrhea and leukopenia.

March 25, 2011 – Ipilimumab – Metastatic Melanoma

The FDA approved ipilimumab (Yervoy) for the treatment of patients with newly diagnosed or previously treated unresectable or metastatic melanoma.¹⁰ Deemed the first checkpoint inhibitor, it was the first approved cancer immunotherapy for melanoma that targeted CTLA-4. At the time of the approval, not only was it the first FDA-approved therapy for unresectable or metastatic melanoma in over a decade, but it was the first and only approved therapy in the disease to demonstrate a significant improvement in OS.

In the phase 3 trial (NCT00094653) that supported the approval, a total of 676 patients with unresectable or metastatic melanoma who were previously treated with at least 1 treatment of aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin were enrolled. Patients were randomly assigned to receive ipilimumab monotherapy, ipilimumab plus glycoprotein 100 (gp100), or gp100 alone.

The median OS was 10 months (95% CI, 8.0-13.8) with ipilimumab, 6 months (95% CI, 5.5-8.7) with gp100, and 10 months (95% CI, 8.5-11.5) with the combination strategy. The P values were .0026 for ipilimumab monotherapy vs gp100 and .0004 for ipilimumab plus gp100 vs gp100.

In the patients who received 3 mg/kg of ipilimumab, severe to fatal immune-mediated AEs included enterocolitis (7%), endocrinopathy (4%), dermatitis (2%), hepatitis (1%), neuropathy (1%), nephritis (1%), and eosinophilia (1%). The most common AE was fatigue (41%). Treatment with ipilimumab was discontinued in 10% of patients.

In tandem with the approval, a Risk Evaluation and Mitigation Strategy consisting of a communication plan was put in place to inform potential prescribers and supportive health care providers about serious AEs associated with ipilimumab.

August 26, 2011 – Crizotinib – ALK+ NSCLC

The FDA approved crizotinib (Xalkori) for the treatment of patients with locally advanced or metastatic non–small cell lung cancer that is ALK positive per an FDA-approved test.¹¹ Concurrently, the Vysis ALK Break-Apart FISH Probe Kit was also approved. Notably, the approval came only 5 years after the first-in-human clinical trials were initiated.

Across 2 trials—a phase 1 trial of crizotinib in any tumor type except leukemia and a phase 2 trial of crizotinib at 250 mg orally twice daily in patients with advanced NSCLC after tumor progression on at least 1 line of chemotherapy—data were collected from patients with ALK-positive NSCLC. Of 116 evaluable patients in the phase 1 trial, the ORR by investigator assessment was 61% (95% CI, 52%-70%), with complete responses (CRs) in 2 patients and partial responses (PRs) in 69; by independent review committee, the ORR was 52% (95% CI, 42%-62%). Of 135 evaluable patients in the phase 2 study, the ORR by investigator assessment was 50% (95% CI, 42%-59%); by independent review committee, the ORR was 42% (95% CI, 32%-52%).

In a clinical review of crizotinib for the Center for Drug Evaluation and Research, Shakun Malik, MD, the reviewing medical officer, wrote on May 5, 2011, “Not all, but [a] majority of these patients had received multiple prior therapies including platinum. The response rate seen in these single arm trials is much superior to any chemotherapeutic regimen even in the first line setting.”¹²

September 4, 2014 – Pembrolizumab – Melanoma

The first approval for pembrolizumab (Keytruda) came in unresectable or metastatic melanoma that progressed following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, in September 2014.¹³ Pembrolizumab was the first anti–PD-1 therapy to be approved by the FDA.

Supporting results for pembrolizumab at the approved dose level—2 mg/kg—were available in 89 patients enrolled in the phase 1b KEYNOTE-001 trial (NCT01295827). The ORR was 24% (95% CI, 15%-34%), with 1 CR and 20 PRs. Of these responders, 86% had ongoing responses with durations ranging from 1.4 months to 8.5 months. Highlighted safety data were that pneumonitis occurred in 2.9% of patients, colitis in 1%, hepatitis in 0.5%, and hypophysitis in 0.5%. Pembrolizumab was also discontinued due to AEs in 6% of patients, and serious AEs occurred in 36%.

Much of the significance of this approval comes in its marking of pembrolizumab’s rise to one of the most prominent oncology drugs of all time. Later, in 2017, pembrolizumab was granted the FDA’s first tumor tissue/site agnostic approval for adult and pediatric patients with metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient solid tumors who progressed following prior treatment and had no satisfactory alternative treatment options.¹⁴

August 30, 2017 – Tisagenlecleucel – Acute Lymphoblastic Leukemia

The FDA approved tisagenlecleucel (tisa-cel; Kymriah) as a treatment for patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.¹⁵ It was the first chimeric antigen receptor (CAR) T-cell immunotherapy to be approved by the FDA, in August 2017.

Results from the single-arm phase 2 ELIANA trial (NCT02435849) showed that tisa-cel yielded a confirmed overall remission rate of 82.5% (95% CI, 70.9%-91.0%), with complete remissions in 63% and complete remissions with incomplete hematological recovery in 19%. The median duration of remission was not reached (range, 1.2-14.1) at the time of approval, and all patients with a confirmed complete remission or complete remission with incomplete hematological recovery were minimal residual disease negative by flow cytometry.

The most common AEs included cytokine release syndrome (CRS), hypogammaglobulinemia, and infections-pathogen unspecified; grade 3/4 AEs were observed in 84% of patients. Notably, serious AEs like CRS, prolonged cytopenia, and infection did occur, and tisa-cel was approved with a Risk Evaluation and Mitigation Strategy. Tocilizumab (Actemra) was approved on the same day as tisa-cel; in patients 2 years or older with severe or life-threatening CRS occurring during CAR T, 1 or 2 doses of tocilizumab led to resolution in 69%.

In an FDA approval summary of tisa-cel, lead author Maura C. O’Leary, from the Center for Biologics Evaluation and Research, of the US FDA, and coauthors acknowledge the “serious and life-threatening toxicity” but affirm that the efficacy is “substantial.”¹⁶ They said, “With a stringent risk mitigation plan in place, the potential benefit from treatment with tisagenlecleucel appears to outweigh the risks for these patients.”

Almost a decade later, various CAR T-cell therapies have been approved across multiple disease states and are renowned for their efficacy and need for only a single infusion.

December 20, 2019 – T-DXd – Breast Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) was approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.¹⁷ T-DXd is a third-generation antibody-drug conjugate that has become one of the primary and most efficacious treatments in HER2-positive and HER2-low breast cancers.

Supporting data for the approval primarily came from the phase 3 DESTINY-Breast01 trial (NCT03248492). The confirmed ORR based on independent central review was 60.3% (95% CI, 52.9%-67.4%), and the median duration of response for confirmed responses was not estimable as of the data cutoff prior to the approval. After an efficacy update, the median duration of response for the 11 patients who responded to treatment was 14.8 months (95% CI, 13.8-16.9).

The T-DXd safety evaluation included data from DESTINY-Breast01 and the phase 1 DS8201-A-J101 trial (NCT02564900); in both trials, patients received at least 1 dose of T-DXd at 5.4 mg/kg. Notably, severe, life-threatening, or fatal interstitial lung disease (ILD) occurred in 9.4%, which were all deemed related to T-DXd. Fatalities due to ILD or pneumonitis occurred in 2.6% of patients, and all were related to the study drug. Neutropenia and left ventricular dysfunction were also concerns.

Now, 7 years later, T-DXd has approval and accelerated approval in 7 HER2-expressing indications across breast and lung cancers and solid tumors.¹⁸

May 28, 2021 – Sotorasib – NSCLC

Sotorasib (Lumakras) was approved for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC).¹⁹ This approval, coming in May 2021, was the first for an agent that successfully targeted KRAS. In the news release announcing the approval, David M. Reese, MD, the executive vice president of Research and Development at Amgen, said, “KRAS has challenged cancer researchers for more than 40 years, with many deeming it as ‘undruggable.’”

A subset of patients in the phase 1/2 CodeBreaK 100 trial (NCT03600883) who had KRAS G12C-mutated NSCLC with disease progression following an immunotherapy and/or chemotherapy achieved an ORR of 36% (95% CI, 28%-45%). The disease control rate was 81% (95% CI, 73%-87%), with a median duration of response of 10 months.

Per safety, diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough were the most common AEs. Sotorasib was permanently discontinued due to AEs by 9% of patients.

As of February 2026, there are only 2 currently approved KRAS inhibitors, the first being sotorasib and the second being adagrasib (Krazati).

February 10, 2026 – Pembrolizumab Combo – Platinum-Resistant Ovarian Cancer

As of the writing of this article, the most recent FDA approval has been for pembrolizumab (Keytruda) and pembrolizumab plus berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with paclitaxel, with or without bevacizumab, for adult patients with PD-L1–expressing, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who have received 1 or 2 prior systemic treatment regimens.²⁰

Coincidental as it may be, there is meaning in that this most recent approval is a regimen containing 3 drugs that have previously been mentioned on this list. If nothing else, it stands to mean that the investigators, researchers, physicians, nurses, and patients of today, who work tirelessly to eradicate cancer, stand on the backs of those who came before them, just as the investigators, physicians, nurses, and patients of the future will do the same.

The past 40 years have seen different eras of therapies emerge into spotlights then fade away into untouched cabinets in cancer centers across the US. Some have remained more prevalent than others, but all were the result of immense work completed by doctors, researchers, scientists, and everyone else involved in the care of patients. It’s only by this work that great developments can be made and greater numbers of patients can survive this dreadful disease.

References

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2. A story of discovery: natural compound helps treat breast and ovarian cancers. National Cancer Institute. March 31, 2015. Accessed February 17, 2026. https://tinyurl.com/4rvpthh5
3. Rituxan. Prescribing information. Genentech; 2021. Accessed February 17, 2026. https://tinyurl.com/yrmzwdby
4. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825-2833. doi:10.1200/JCO.1998.16.8.2825
5. Trastuzumab approval letter. FDA. September 25, 1998. Accessed February 17, 2026. https://tinyurl.com/y7c3mnf6
6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. doi:10.1056/NEJM200103153441101
7. Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8(5):935-942.
8. Approval package for bevacizumab. Center for Drug Evaluation and Research. February 26, 2004. Accessed February 18, 2026. https://tinyurl.com/mpvey9uc
9. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342. doi:10.1056/NEJMoa032691
10. FDA approves Yervoy (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. News release. Bristol Myers Squibb. March 25, 2011. Accessed February 18, 2026. https://tinyurl.com/mr36xheb
11. Malik SM, Maher VE, Bijwaard KE, et al. U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Clin Cancer Res. 2014;20(8):2029-2034. doi:10.1158/1078-0432.CCR-13-3077
12. Medical review of crizotinib. Center for Drug Evaluation and Research. May 5, 2011. Accessed February 18, 2026. https://tinyurl.com/5fychkst
13. Merck receives accelerated approval of Keytruda (pembrolizumab), the first FDA-approved anti-PD-1 therapy. News release. Merck. September 4, 2014. Accessed February 18, 2026. https://tinyurl.com/bumn74ya
14. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Updated May 30, 2017. Accessed February 18, 2026. https://tinyurl.com/mv4sezfw
15. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. August 30, 2017. Updated September 7, 2017. Accessed February 18, 2026. https://tinyurl.com/bderdcyh
16. O’Leary MC, Lu X, Huang Y, et al. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25(4):1142-1146. doi:10.1158/1078-0432.CCR-18-2035
17. Narayan P, Osgood CL, Singh H, et al. FDA approval summary: fam-trastuzumab deruxtecan-nxki for the treatment of unresectable or metastatic HER2-positive breast cancer. Clin Cancer Res. 2021;27(16):4478-4485. doi:10.1158/1078-0432.CCR-20-4557
18. Stewart J. Enhertu FDA approval history. Drugs.com. Updated December 16, 2025. Accessed February 18, 2026. https://tinyurl.com/w375n5v7
19. FDA approves Lumakras (sotorasib), the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. Amgen. May 28, 2021. Accessed February 18, 2026. https://tinyurl.com/4zwdhf5p
20. FDA approves pembrolizumab with paclitaxel for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. FDA. February 10, 2026. Accessed February 18, 2026. https://tinyurl.com/ydzhnzha