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of data readouts in ovarian cancer including that with the PARP inhibitor niraparib (Zejula), the novel agent gotistobart, and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), which recently received a tumor-agnostic FDA approval, the tides are also changing in cervical and endometrial cancers with the addition of checkpoint inhibitors to traditional chemoradiotherapy and integration of other immunotherapy-based approaches, respectively.

During the 2024 European Society for Medical Oncology (ESMO) Congress, 

 was onsite in Barcelona, Spain, and filmed a 

 with leading experts in the field of gynecologic oncology. During the discussion, the investigators highlighted multiple practice-altering clinical trial updates presented over the course of the meeting and beyond in ovarian, cervical, and endometrial cancers.

“It has been an amazing year [in gynecologic cancer research], kicking off with the Society of Gynecologic Oncology Meeting on Women’s Cancer, the American Society of Clinical Oncology meetings, and now the ESMO Congress,” 

said. “We have learned so much and now we need to look at all these emerging therapies and explore the future directions of the management of these cancers and [interrogate] what we do in the clinic.”

Updated Data Provide Additional Options in Ovarian Cancer

In June 2020, the FDA approved niraparib as maintenance therapy in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer following a complete or partial response to frontline platinum-based chemotherapy. The regulatory decision was supported by findings from the phase 3 PRIMA trial (NCT02655016).

 “PRIMA met its primary end point, which was progression-free survival [PFS], both in the intention-to-treat group as well as in the 

-mutated [subgroup], so it received approval for all comers. We’ve all been awaiting the long-term overall survival [OS] data and finally we saw those [at the 2024 ESMO Congress],” 

Findings from the final OS analysis of PRIMA presented during the 2024 ESMO Congress demonstrated that patients with newly diagnosed advanced ovarian cancer with a complete or partial response to frontline platinum-based chemotherapy achieved a median OS of 46.6 months vs 48.8 months with niraparib (n = 487) or matched placebo (n = 246), respectively (HR, 1.01; 95% CI, 0.84-1.23; 

 = .8834). However, at a median follow-up of 6.2 years, niraparib continued to display a sustained PFS benefit vs placebo (HR, 0.66; 95% CI, 0.55-0.78).

“We didn’t necessarily see an [OS] benefit, but there are many reasons for that,” Pothuri said. “It’s important to recognize that there’s crossover and patients with ovarian cancer [often] receive so many subsequent lines [of treatment]. We should be pleased that we didn’t see any survival decrement, and I will continue using niraparib in my practice.”

For patients with platinum-resistant disease, the investigational pH-sensitive CTLA-4–preserving antibody gotistobart is emerging as a potential therapeutic option. Gotistobart is being investigated in combination with pembrolizumab (Keytruda) in the phase 2 PRESERVE-004/GOG-3081 study (NCT05446298). Preliminary findings presented during the 2024 ESMO Congress showed that the combination led to an unconfirmed objective response rate (ORR) of 25.0% (95% CI, 11.5%-43.4%) and 27.6% (95% CI, 12.7%-47.2%) among patients treated with the 1-mg/kg (n = 32) and 2-mg/kg (n = 29) dose levels of gotistobart.

“PARP inhibitor resistance is important in this era; we’re seeing many patients [who are] not as susceptible to retreatment with platinum,” Pothuri commented. “There are many reasons for PARP [inhibitor] resistance, including reversion mutations, replication, and fork stabilization. There are some [interesting] new therapies that may overcome PARP [inhibitor] resistance.”

Another option for patients with gynecologic malignancies is the antibody-drug conjugate (ADC) T-DXd. T-DXd received approval from the FDA in April 2024 in adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. The approval was supported by data from the phase 2 DESTINY-PanTumor02 trial (NCT04482309), which included patients with gynecologic cancers.

“One of the biggest changes that [affected] practice [this past] year was the approval of T-DXd in the tumor-agnostic category for patients who with HER2 [IHC] 3+ staining based on gastric scoring,” Secord said. “Then the National Comprehensive Cancer Network [guidelines] came out, and, for many of our cancers, they also allowed use of that therapy in individuals who had [IHC] 2+ staining.”

Findings from DESTINY-PanTumor02 showed that patients with ovarian (n = 40), cervical (n = 40), or endometrial cancer (n = 40) achieved ORRs by independent central review of 42.5%, 40.0%, and 52.5%, respectively. The respective median durations of response (DORs) were 11.3 months (95% CI, 4.1-not estimable [NE]), 9.8 months (95% CI, 4.2-NE), and not reached (95% CI, 9.9-NE).

“[T-DXd] is a total game changer; I’m excited, but don’t want to get too excited, because we have some [other] good medications that went through phase 2 and 3 [study], so I’m reserving it for later lines of therapy,” 

, said. “When one [considers] some of the heterogeneity and the scoring, there’s a lot of work to be done. Our pathologists say that when we’re asking for ovarian, endometrial, and cervical [scoring] that they’re using more of an endometrial serous [scoring method], which [has] a 30% positivity [rate], so we may be missing some patients. We need to communicate with our pathologists to make sure that we’re getting an IHC [test] to be able to use this medication.”

Targeted Therapies Solidify Their Place in Cervical Cancer

The standard of care for patients with locally advanced cervical cancer has traditionally been external beam radiotherapy with concurrent chemotherapy and brachytherapy. However, recent clinical trial updates have shown the benefit of checkpoint inhibitors for these patients, both in addition to chemotherapy and as monotherapy.

“When we [consider] advanced cervical cancer, that’s getting out of the surgical realm,” 

, said. “[The standard of care] has been chemoradiation for a long period of time. I examine the patient’s PET-CT scan to see [whether] they’re diffusely metastatic [because] that’s going to help determine whether a patient is going to receive chemotherapy [plus immunotherapy] with radiation therapy or switch over to possibly a chemotherapy/bevacizumab [Avastin]/immunotherapy regimen. Many of these patients will present with advanced-stage disease and may be able to tolerate some of this treatment. The exam, the PET-CT scan, and the staging of the patients define where their disease [is] and [are] going to tailor [treatment for] that patient.”

During the first presidential symposium of the 2024 ESMO Congress, investigators presented updated findings from the phase 3 KEYNOTE-A18/ENGOT-cx11/GOG-3047 trial (NCT04221945), which examined pembrolizumab in combination with chemoradiotherapy in FIGO 2014 stage IB2 to IIB node-positive or stage III to IVA node-positive or node-negative cervical cancer. Prior data from the study supported the January 2024 FDA approval of the combination in FIGO 2014 stage III to IVA cervical cancer.

At the second interim analysis, at a median follow-up of 29.9 months (range, 12.8-43.0), patients who received pembrolizumab plus chemoradiotherapy followed by pembrolizumab maintenance (n = 529) experienced a 32% reduction in the risk of disease progression or death compared with those who received placebo plus chemoradiotherapy (n = 531; HR, 0.68; 95% CI, 0.56-0.84). In terms of the other primary end point of OS, patients experienced a 33% reduction in the risk of death in the investigational arm vs the placebo arm (HR, 0.67; 95% CI, 0.50-0.90; 

 = .0040). The 36-month PFS rates were 69.3% (95% CI, 62.7%-75.0%) vs 56.9% (95% CI, 50.4%-62.9%), respectively, and the 36-month OS rates were 82.6% (95% CI, 78.4%-86.1%) vs 74.8% (95% CI, 70.1%-78.8%), respectively.

“This study shows the benefit of adding pembrolizumab to chemo[radio]therapy with maintenance pembrolizumab afterward [in terms of] PFS and OS,” Thaker said. “The key for us to cure patients is in the up-front setting, so [these data are] very encouraging. At least in the US, we can use it already for stage III and IV [disease]. It will be interesting to see how the presentation may change for stage I and II [disease] because the forest plots are still evolving.”

Following frontline treatment, a therapeutic option for patients with cervical cancer who experience disease progression is the ADC tisotumab vedotin-tftv (Tivdak). In April 2024, the agent received full approval from the FDA in recurrent or metastatic cervical cancer following disease progression on or after chemotherapy after receiving accelerated approval for the same indication in September 2021.

“The payload of tisotumab vedotin is monomethyl auristatin E, which is like a taxane. It’s a tubulin-disrupting agent and has a unique target, tissue factor, which is highly expressed in cervical cancer, and you don’t need a biomarker. That’s a very important point to make [because] no biomarker is highly expressed in cervical cancer,” 

The phase 3 innovaTV 301 trial (NCT04697628), which supported the approval, evaluated tisotumab vedotin vs investigator’s choice of chemotherapy as second- or third-line therapy in recurrent or metastatic cervical cancer. Updated data from the study published in July 2024 in the

demonstrated that patients who received the ADC (n = 253) achieved a median OS of 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7) among patients in the chemotherapy arm (n = 249; HR, 0.70; 95% CI, 0.54-0.89; 2-sided 

 = .004). The median PFS was 4.2 months (95% CI, 4.0-4.4) vs 2.9 months (95% CI, 2.6-3.1), respectively (HR, 0.67; 95% CI, 0.54-0.82; 2-sided 

“It definitely takes work [to manage the toxicity profile of tisotumab vedotin],” Chase noted. “There are 3 toxicities to be aware of: peripheral neuropathy, hemorrhage, and ocular toxicity. This drug requires active prophylaxis for ocular disease, so the patient has to see an eye care provider before they start treatment. The patient has to have eye drops, both vasoconstrictors and steroids, as well as lubricating eye drops, and it takes a certain amount of sophistication to get into the eye care provider to use the drop.”

Immunotherapy Emerges in Endometrial Cancer

The panelists concluded their discussion by shifting their focus to updates in the endometrial cancer treatment landscape. “[Recent data] have cemented that in mismatch repair–deficient [dMMR] patients we should be using chemotherapy and immunotherapy, because the PFS and OS curves are beautiful; those are the curves we all dream of as clinical trialists. Even in our mismatch repair–proficient [pMMR] patients, there is a benefit [but] not to the same extent,” Thaker commented.

The phase 3 RUBY trial (NCT03981796) examined dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel in patients with primary advanced or recurrent endometrial cancer. Previous findings from part 1 the study showed that it met its co–primary end point, demonstrating a PFS benefit with the addition of dostarlimab to chemotherapy in patients with dMMR/microsatellite instability–high (MSI-H) disease (HR, 0.28; 95% CI, 0.16

 < .0001) and in the overall population (HR, 0.64; 95% CI, 0.51

“It’s a story that we’re building on and it’s very exciting,” Krivak said. “We took a disease that was once treated with surgery and radiation [where] chemotherapy wasn’t [considered] and we’re adding chemotherapy [with] biologic therapy. We have to build off this, but it’s great for patients and clinical investigators.”

In terms of the other co–primary end point of OS, updated data from part 1 of RUBY showed that patients in the dostarlimab arm (n = 245) achieved a median OS of 44.6 months compared with 28.2 months in the placebo arm (n = 249; HR, 0.69; 95% CI, 0.54

 = .0020). Moreover, in a prespecified exploratory analysis patients with dMMR/MSI-H (HR, 0.32; 95% CI, 0.17

 = .0002) and pMMR/microsatellite stable disease (HR, 0.79; 95% CI, 0.60

 = 0.0493) experienced a trend toward an OS benefit with dostarlimab vs placebo.

Findings from the RUBY trial led to the FDA expanding the indication for dostarlimab in combination with carboplatin and paclitaxel, followed by dostarlimab monotherapy for the treatment of adult patients with primary advanced or recurrent endometrial cancer in August 2024. The regimen was previously indicated in dMMR/MSI-H advanced or recurrent endometrial cancer based on prior findings from part 1 of the study.

“In the summer [of 2024] data from the [phase 3] NRG-GY018 study [NCT03914612] led to the FDA approval of pembrolizumab [with chemotherapy], but that was for an all-comers indication,” Chase said. “Then we got an all-comers [indication] for the RUBY trial. It didn’t change [my practice] but gave me more support if I wanted to use dostarlimab in a pMMR patient population. In the pMMR population, if I can improve, reduce, or even stabilize that patient’s disease, I’ll be happy to use immunotherapy.”

Another checkpoint inhibitor/chemotherapy combination regimen was examined in patients with treatment-naive advanced endometrial cancer in the phase 3 DUO-E trial (NCT04269200). DUO-E evaluated durvalumab (Imfinzi) plus carboplatin and paclitaxel followed by durvalumab maintenance therapy with (n = 239) or without (n = 238) olaparib (Lynparza). The primary end points were PFS in the durvalumab vs control (n = 241) arms and the durvalumab plus olaparib vs control arms.

Findings from DUO-E showed that patients who received durvalumab (HR, 0.71; 95% CI, 0.57-0.89; 

 = .003) and durvalumab plus olaparib (HR, 0.55; 95% CI, 0.43-0.69; 

 < .0001) with chemotherapy experienced a significant PFS benefit vs chemotherapy alone. This PFS benefit was also observed in patients with dMMR disease with durvalumab (n = 46) vs chemotherapy (n = 49; HR, 0.42; 95% CI, 0.22-0.80) and durvalumab plus olaparib (n = 48) vs chemotherapy (HR, 0.41; 95% CI, 0.21-0.75). There was also a smaller PFS benefit with durvalumab (n = 192) vs chemotherapy (n = 192; HR, 0.77; 95% CI, 0.60-0.97) and durvalumab plus olaparib (n = 191) vs chemotherapy (HR, 0.57; 95% CI, 0.44-0.73) in the pMMR subgroup.

Data from DUO-E supported the June 2024 FDA approval of durvalumab plus carboplatin and paclitaxel followed by durvalumab monotherapy for the treatment of patients with dMMR primary advanced or recurrent endometrial cancer.

“These trials show that immunotherapy [is effective] in patients with recurrent, advanced endometrial cancer, definitely in the dMMR group and with some heavy signals that it may be beneficial in patients with pMMR [disease] too. [This is] a game changer,” Secord noted.

During the 2024 ESMO Congress, investigators presented findings from 2 phase 2 studies evaluating investigational TROP2-directed ADCs in endometrial and ovarian cancer: TROPION-PanTumor03 (NCT05489211) examining datopotamab deruxtecan (Dato-DXd) and KL264-I-01 (NCT04152499) of sacituzumab tirumotecan. TROP2 is highly expressed in ovarian and endometrial cancers, making it an attractive therapeutic target for the next generation of ADCs.

At a median follow-up of 13.6 months (range, 2.1-19.6), patients with advanced or metastatic endometrial cancer with disease progression on at least 1 but no more than 2 lines of chemotherapy in the TROPION-PanTumor03 trial who received Dato-DXd (n = 40) experienced a confirmed ORR of 27.5% (95% CI, 14.6%-43.9%), with a 2.5% complete response rate. The median DOR and PFS were 16.4 months (95% CI, 7.1-not calculable [NC]) and 6.3 months (95% CI, 2.8-NC), respectively.

In KL264-I-01, patients with advanced endometrial cancer who received at least 1 prior line of platinum-based chemotherapy and prior anti–PD-L1 therapy, if dMMR/MSI-H, treated with sacituzumab tirumotecan (n = 44) achieved a confirmed ORR of 27.3%, including 41.7% among patients with a TROP2 H-score above 200. The median DOR and PFS were 5.7 months (range, 3.8-7.4+) and 5.7 months (95% CI, 3.7-9.4), respectively. Sacituzumab tirumotecan is being evaluated vs physician’s choice of chemotherapy in patients with endometrial cancer who received prior platinum-based chemotherapy and immunotherapy in the phase 3 TroFuse-005 study (NCT06132958).

“These data [with the TROP2-directed ADCs] are very exciting,” Krivak said. “We’re [considering] the responses, DOR, and the [adverse effects]. As we learn more about these medications, we’ll [primarily consider] efficacy, interstitial lung disease, nausea/vomiting, and hematologic toxicity, then [we will] be able to select different medications for each patient based upon their prior toxicity. We’re starting to see the phase 3 trials open that are going to help differentiate some of the patient populations that are going to benefit, but there’s no doubt that TROP2 is an exciting target to tackle in endometrial cancer.”

FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed October 2, 2024. bit.ly/47UTXVc

González-Martín A, PothuriB, Barretina Ginesta MP, et al. Final overall survival (OS) in patients (pts) with newly diagnosed advanced ovarian cancer (aOC) treated with niraparib (nir) first-line (1L) maintenance: results from PRIMA/ENGOT-OV26/GOG-3012. 

. 2024;35(suppl 2):S1222-S1223. doi:10.1016/j.annonc.2024.08.2268

Barlin JN, Lim PC, Pepin JT, et al. A randomized, phase II, dose optimization of gotistobart, a pH-sensitive anti-CTLA-4, in combination with standard dose pembrolizumab in platinum-resistant recurrent ovarian cancer: safety, efficacy and dose optimization (PRESERVE-004/GOG-3081). 

. 2024;35(suppl 2):S1224-S1225. doi:10.1016/j.annonc.2024.08.2271

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed October 2, 2024. bit.ly/4ep3pm3

Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. 

. 2023;41(suppl 17):LBA3000. doi:10.1200/JCO.2023.41.17_suppl.LBA3000

Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study.

. 2024;35(suppl 2):S544. doi:10.1016/j.annonc.2024.08.771

FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed October 1, 2024. bit.ly/3zT5pno

FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. April 29, 2024. Accessed October 1, 2024. bit.ly/4erFEtp

Vergote I, González-Martín A, Fujiwara K, et al. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. 

. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811

Powell MA, Bjørge L, Willmott, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. 

. 2024;35(8):728-738. doi:10.1016/j.annonc.2024.05.546

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed September 24, 2024. bit.ly/3Y7nIif

Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. 

. 2024;42(3):283-299. doi:10.1200/JCO.23.02132

FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer.FDA. June 14, 2024. Accessed September 24, 2024. bit.ly/47Rk7bb

OakninA, Ang JE, Rha SY, et al. Datopotamab deruxtecan (Dato-DXd) in patients with endometrial (EC) or ovarian cancer (OC): results from the phase II TROPION-PanTumor03 study. 

. 2024;35(suppl 2):S547-S548. doi:10.1016/j.annonc.2024.08.776

Wang D, Wang K, An R, et al. Safety and efficacy of sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced endometrial carcinoma (EC) and ovarian cancer (OC) from a phase II study. 

. 2024;35(suppl 2):S548. doi:10.1016/j.annonc.2024.08.777

Articles

The landscape of gynecologic oncology is evolving with significant advancements in ovarian, cervical, and endometrial cancers. Notable developments include the use of PARP inhibitors like niraparib, novel agents such as gotistobart, and the tumor-agnostic approval of T-DXd. Checkpoint inhibitors are enhancing treatment regimens in cervical and endometrial cancers, offering improved progression-free survival and overall survival outcomes. The integration of immunotherapy and targeted therapies is reshaping treatment paradigms, providing new options for patients with advanced or resistant disease, and highlighting the importance of personalized treatment strategies.

Experts in gynecologic oncology highlight multiple practice-altering clinical trial updates presented at ESMO and beyond in ovarian, cervical, and endometrial cancers.

Gynecologic Cancer Paradigm Sees Huge Gains With FDA-Approved Regimens

If asked to do so, it would be easy to provide a list of clinical issues in critical need of increased attention by the oncology community. However, within that list, it would be difficult to suggest any single item is of greater importance than the need to revisit our basic concepts of how we define optimal doses and schedules, as well as appropriate modification schema for antineoplastic agents, with acknowledgment of the essential balance between efficacy and toxicity for this broad class of drugs.

In the earliest days of the modern chemotherapeutic era, the dose- and schedule-related questions were simply defined, subsequently relatively easily addressed, and the most relevant toxicity metrics (eg, hematologic blood counts, renal and hepatic function tests) were not difficult to obtain. A standard toxicity scale (grades 1-4) routinely employed in clinical cancer investigative efforts for multiple possible adverse effects (AEs) added to the convenience of establishing an accepted language among investigators for the negative effects of the therapy. Even the less common, but potentially more devastating effect of anthracyclines on the heart could be monitored and quantified by routine noninvasive examination of cardiac function tests.

Measures of efficacy were also straightforward and included the objective response rate (in phase 2 and 3 trials) and survival outcomes (progression-free and overall) in randomized controlled studies (or far less convincingly, experimental data compared with contemporaneous or historical controls).

In this era, the strategy was to administer treatment (in most settings intravenously and intermittently) at the maximum tolerated dose (MTD), as determined through careful examination of the toxicity severity metrics. The severity of AEs in each treatment cycle, the observed time to recovery of normal hematopoietic function, and other pathophysiologic events were considered in the definition of MTD.

Rather arbitrary dose modification schemas (eg, initial 25% dose reduction) were routinely employed in the face of excessive AEs or delayed recovery of the measured toxicity parameters. This strategy was usually deemed successful in this era of intermittent systemic cytotoxic therapy, which generally did not exceed between 4 and 6 months in total duration, most often due to rather rapid evidence of disease progression or lack of evidence of a clinically meaningful response in the presence of unacceptable toxicity.

What has been outlined above is a relatively simple, standardized process that was fairly easily monitored with routine laboratory testing. Further, because it was not realistically possible to safely administer even higher drug doses without some form of bone marrow support, one could confidently argue that an alternative dosing strategy would be unable to produce a superior effect on the growing cancer.

Where does one begin to fix this state of affairs?

First and perhaps the most relevant comment is the decision to focus on the MTD assumes this is the 

 for achieving the desired anticancer effect. What if treatment delivered at 80% or even 50% of the declared MTD of an individual drug or combination chemotherapy produced an equivalent degree of tumor shrinkage while reducing the risk of serious or even only moderately bothersome AEs? What if it also permitted a particular regimen to be administered over a more 

, possibly prolonging the favorable effects of the therapeutic regimen?

Second, lower doses of an effective antineoplastic would likely result in reduced costs to hospitals, oncology practices, and, most importantly, individual patients. This point is increasingly relevant in an era of simply staggering financial implications of this form of therapy, including the effect of drug wastage.

Finally, the management of cancer has rather dramatically changed over the past several decades, in the types of agents administered (small molecule targeted and immunotherapeutic agents), anticipated AEs (bone marrow suppression/emesis not necessarily the most severe toxicity), duration of treatment (increasingly common to employ an extended 

), and in method of delivery (continuous oral vs intermittent intravenous).

Further, as advanced cancers are increasingly recognized to be serious but more chronic conditions resulting from the delivery of multiple sequential effective therapeutic strategies, and where survival today may be measured in years rather than months, the cumulative influence of AEs on normal organ function and a patient’s quality of life over this extended period must be considered.

Therefore, a continued focus on dose and schedule that ignores this reality and fails to consider the well-recognized fact that research subjects unfortunately rarely reflect noninvestigative cancer patient demographics (eg, age, presence of relevant comorbidities, medications commonly employed in older individuals) would appear to be a serious error.

Consider for a moment the required decision-making process of a busy community oncologist (most patients with cancer in the US receive their care at oncology practices) seeing for the first time a 75-year-old individual with newly diagnosed metastatic cancer. Their performance status is adequate for systemic therapy, and the patient desires to at least initially pursue an aggressive approach to disease control. Further, the individual is objectively overweight, was until 5 years ago a moderately heavy smoker, has a long history of well-controlled but medication-dependent diabetes and hypertension, and also experienced a mild cerebrovascular event (all signs now resolved) 8 months prior to the diagnosis of malignancy. Today, there is nothing about this brief medical history that is strikingly unusual for patients with advanced cancer in the United States.

Multiple questions regarding the optimal care of this individual can be asked. For example, should concern for the risk of toxicity lead the oncologist to initiate drug therapy at a reduced dose? Will this compromise the treatment’s efficacy? If a dose reduction is required due to observed AEs after the first cycle, should a standard modification paradigm be employed, or should a greater change be instituted due to heightened concerns in this older individual with comorbidities?

The broader question to be addressed is whether as a society we can do a better job defining the optimal use of antineoplastic regimens (single-agent and combination strategies). This includes the following critical items:

The recognition by the pharmaceutical industry, relevant governmental agencies, and the cancer research community that participants in antineoplastic drug trials designed for regulatory approval simply 

do not appropriately represent the population of individuals treated in the noninvestigative setting

, which seriously impairs the ability to adequately define potential toxicities and their appropriate amelioration.

The continued focus on determining the MTD as a strategy for drug approval does not necessarily define the most appropriate method for 

. Fortunately, there is evidence that the FDA is increasingly aware of this conundrum and taking action to improve the situation.

 But greater efforts in this arena are clearly needed.

Shah VS, Irvine C, McWilliams RR, et al. Reducing cancer drug cost: 3-year analysis of automated dose rounding in electronic health records. 

. Published online August 5, 2024. doi:10.1200/ OP.23.00688

Shah M, Rahman A, Theoret MR, Pazdur R. The drug-dosing conundrum in oncology – when less is more. 

. 2021;385(16):1445-1447. doi:10.1056/NEJMp2109826

The oncology community must reconsider its approach to defining optimal dosing and scheduling of antineoplastic agents.

Vol. 25/No. 14 | Oncology Live®

Gynecologic Cancer Paradigm Sees Huge Gains With FDA-Approved Regimens

A Call to Action: Determining Optimal Dose, Schedule, and Appropriate Modifications for Antineoplastic Pharmaceutical Agents