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As a result of the Affordable Care Act’s Medicaid expansion, positive trends are becoming apparent regarding mortality rates for patients with cancer living in the states that have adopted Medicaid expansion. Following its 2010 enactment, the bill expanded coverage to adults under the age of 65 years with an income of up to 138% of the federal poverty level,

 which in 2023 is $20,120 for an individual.

 As of July 2023, 40 states and Washington, DC, have adopted Medicaid expansion and North Carolina has adopted but not implemented it.

Recently published data collected at the state level of 17,370 observations from the Surveillance, Epidemiology, and End Results Program and the National Center for Health Statistics databases showed that Medicaid expansion was associated with a decrease in distant stage cancer incidence (adjusted odds ratio [OR], 0.967; 95% CI, 0.943-0.992; 

 = .01) and cancer mortality (adjusted OR, 0.965; 95% CI, 0.936-0.995; 

The data revealed that distant stage cancer incidence was found to mediate 58.4% of expansion-associated changes in cancer mortality overall (

, lead study author Justin Barnes, MD, explained “is important, as it helps clarify part of the mechanism of how Medicaid expansion improves cancer outcomes. It [does this] by shifting the stage of diagnosis, at least in part, leading to fewer individuals who are diagnosed with a more advanced and potentially incurable disease.”

Barnes, who is the assistant chief resident in the Department of Radiation Oncology at the Washington University School of Medicine in St Louis, Missouri, added that “Medicaid expansion was associated with decreased distant stage cancer incidence rates and decreased cancer mortality rates, which translates to approximately 2600 averted distant stage cancer diagnoses and approximately 1600 averted cancer deaths.”

Data also revealed that statistically significant Medicaid expansion–associated decreases in cancer mortality were seen for patients with breast (OR, 0.974; 95% CI, 0.950-0.999), cervix (OR, 0.921; 95% CI, 0.869-0.975), and liver (OR, 0.934; 95% CI, 0.879-0.993) cancers, as well as for White patients (OR, 0.971; 95% CI, 0.948-0.995).

An additional study used an adjusted difference-in-differences model estimate for incidence of gastric cancer, which demonstrated that there were significantly fewer new cases of gastric cancer per year in Medicaid expansion states, at –1.6 per 1,000,000 individuals (95% CI, 0.02-0.35; P = .083).

Shria Kumar, MD, MSCE, an assistant professor of medicine at the University of Miami Miller School of Medicine in Florida, explained in an interview with 

, that as “gastric cancer incidence expansion states had on average 1.6 fewer new cases of gastric cancer per million adults every year, that means in California there would be 32 fewer cases of gastric cancer each year and in New York state there would be 16 fewer cases.”

The model also showed that there was no significant association between Medicaid expansion and gastric cancer mortality at 0.46 cases per 1,000,000 individuals (95% CI, 0.08-0.17; 

 = .46), as well as esophageal cancer incidence at 0.8 cases per 1,000,000 individuals (95% CI, 0.08-0.24; 

 = .33), and esophageal mortality at 1.0 cases per 1,000,000 individuals (95% CI, 0.06-0.26; P = .21).

However, Kumar said that although “esophageal cancer mortality and incidence results weren’t significant, already within a few years [of having Medicaid expansion], we’re starting to see these developing trends of improvement.” Kumar also explained that regarding the gastric and esophageal data,

 “it’s important [to note that the] study was limited to just a few years of Medicaid expansion. I would venture to guess that with more time, we’re going to see significant differences in mortality for both cancers, as well as incidence for esophageal cancer. The reason for that is not just prevention, motivational interviewing, and so forth, but for esophageal cancer, we have screening recommendations that require access to health care.”

Outside of tumor-specific analyses, data from additional studies showed that the 2-year overall survival (OS) rate was increased by 1.5% (95% CI, 0.37-2.64) in expansion states relative to nonexpansion states for pediatric patients.

 Additionally, the 2-year OS rate for young adults aged 18 to 39 years increased, with those in expansion (n = 213,881) states experiencing rates of 90.39% pre-expansion to 91.85% post-expansion vs 88.98% pre-expansion to 90.07% post-expansion for those in nonexpansion states (n = 131,532).

When evaluating sociodemographic characteristics from 2010 of individuals in nonexpansion states (n = 12) vs expansion states (n = 19), investigators found that 17.9% of those in nonexpansion states were Black compared with 11.0% in expansion states (

 = .02). Significant differences were also observed in expansion vs nonexpansion states regarding how many individuals were diabetic (10.1% vs 9.0%; 

= .03), and living below the poverty line (17.6% vs 15.0%, 

“[This is] striking, as these are states that haven’t opted into Medicaid expansion, [and] the medical conditions mentioned need health care,” Kumar said. “It’s critically important to make sure we are offering individuals who are of historically disadvantaged groups accessible and affordable medical care.”

Kumar noted that limited access to reliable health insurance leads to a lack of access to preventative services, resulting in fewer diagnoses overall and more late-stage diagnoses. “I cannot emphasize how important screening is, especially for the main luminal gastrointestinal cancers—esophagus, gastric, and colon. The difference between an early-stage diagnosis and a late-stage diagnosis is significant not just in terms of mortality but also in terms of what treatment patients receive, how expensive those treatments are, [and] what it means for surrounding friends, family, and support systems.”

Barnes echoed this explaining that, “I have unfortunately seen many patients who have delayed seeking care due to lack of insurance and worries about costs. In some cases, that’s led to more advanced cancer that is symptomatic, impacting quality of life, harder to treat possibly requiring longer and more intensive and toxic treatments, and [their disease is] less likely to be cured. With more patients with Medicaid coming in the door, we are hopefully avoiding some of those more advanced presentations and can get patients the treatment they need.”

As preventative measures such as screening remain crucial, additional challenges have arisen as individuals may face Medicaid re-enrollment difficulties in the future. Because of the COVID-19 pandemic, Congress enacted the Families First Coronavirus Response Act, which required that Medicaid keep individuals continuously enrolled;

 however, as of April 1, 2023, Congress declared that Medicaid programs must go back to federal rules.

 With this, millions of patients had their coverage affected.

“In the past few months, we’ve seen over 5 million Medicaid enrollees who have been disenrolled with the unwinding of the public health emergency, which previously allowed individuals who qualify for Medicaid to remain continuously enrolled,” Barnes said. “There are 5 million so far, and an additional 10 million [individuals] are projected to be disenrolled over the next several months. This could have disastrous consequences from a cancer perspective.”

However, Barnes explained that “some of this could be mitigated through consideration of Medicaid expansion in those 10 states that haven’t yet expanded, especially because approximately a half million [individuals] who will lose coverage live in those states. They are projected to fall into a coverage gap, which means they live in these states, don’t have access to expanded Medicaid eligibility, and their income is too high to qualify for Medicaid but not high enough to qualify for subsidies through the marketplace. We need to figure out how to best support the disenrolled individuals and reduce some of the administrative disenrollments for [those] who are still eligible for Medicaid.”

Barnes noted that resources such as the American Cancer Society Cancer Action Network, which he regularly is in touch with, help him find ways to advocate for patients in Missouri. He also highlighted that the American Society of Clinical Oncology (ASCO) and American Society for Radiation Oncology (ASTRO) will often work to develop initiatives on proposed legislation or issues facing care on their platforms. These proposals also allow individuals to connect with state representatives, and following determination of the proper representative, ASCO/ASTRO will provide a letter template with relevant data written out, allowing for a convenient direct message to be sent to the representative.

“For Medicaid expansion enrollment, you need state legislature as well as governor authorization,” Kumar said. “[In] the years since we conducted our study, more states have opted into Medicaid expansion, and a lot of that has been because of health care advocacy groups. They have been a big force in ensuring more individuals get access to health care.”

Barnes said the message is simple: “Medicaid expansion can save lives and prevent cancer deaths. When we think about our health care system on a state or national level, these data add to an ever-growing body of evidence that increasing insurance coverage, especially to more vulnerable populations such as those who are eligible for Medicaid, can increase access to care and improve cancer outcomes.” 

Hotca A, Bloom JR, Runnels J, et al. The impact of Medicaid expansion on patients with cancer in the United States: a review. 

. 2023;30(7):6362-6373. doi:10.3390/curroncol30070469

Status of state Medicaid expansion decisions: interactive map. Kaiser Family Foundation. July 27, 2023. Accessed September 8, 2023. https://www.kff.org/medicaid/issue-brief/status-of-state-medicaid-expansion-decisions-interactive-map/ 

Barnes JM, Johnson KJ, Osazuwa-Peters N, Yabroff KR, Chino F. Changes in cancer mortality after Medicaid expansion and the role of stage at diagnosis. 

. 2023;115(8):962-970. doi:10.1093/jnci/djad094

Niroomand E, Kumar SR, Goldberg D, Kumar S. Impact of Medicaid expansion on incidence and mortality from gastric and esophageal cancer. 

. 2023;68(4):1178-1186. doi:10.1007/s10620-022-07659-6

Ji X, Shi KS, Mertens AC, et al. Survival in young adults with cancer is associated with Medicaid expansion through the Affordable Care Act. 

. 2023;41(10):1909-1920. doi:10.1200/JCO.22.01742

Tolbert J, Ammula M. 10 things to know about the unwinding of the Medicaid continuous enrollment provision. Kaiser Family Foundation. June 9, 2023. Accessed September 8, 2023. https://www.kff.org/medicaid/issue-brief/10-things-to-know-about-the-unwinding-of-the-medicaid-continuous-enrollment-provision/

Eligibility unwinding. New Jersey Department of Human Services. Accessed September 8, 2023. https://nj.gov/humanservices/dmahs/staycoverednj/unwinding/

Articles

As a result of the Affordable Care Act’s Medicaid expansion, positive trends are becoming apparent regarding mortality rates for patients with cancer living in the states that have adopted Medicaid expansion. 

Data Reveal Medicaid Expansion May Result in Mortality Rate Reductions for Patients With Cancer

Drug development is a difficult and ever-changing process, with new agents being developed by industry and academic partners. Still, the average time from investiga- tor new drug filing to final new drug application approval is 8.7 years because of the need for vetting in the preclinical and clinical trial setting.

 Although the process is rigorous to provide approval at a faster pace, in general, the process still takes several years of clinical development before being approved for use in the clinical setting.

The traditional trajectory for early-phase cancer drug development is typically conducted in patients who are heavily pretreated, as novel investigational agents are used when no other stan- dard-of-care therapies exist. 

Novel trial designs have been used, with close collaborations between clinicians, laboratory researchers, and industry partners, such as single-patient trials (N-of-1) trials,

 to provide patients with new therapeutic options when no other treatments exist. For example, N-of-1 trials were conducted in patients receiving larotrectinib (Vitrakvi) for TRK fusion–positive cancers, as well as LOXO-292 (now approved by the FDA as selpercatinib [Retevmo]) for patients with RET alterations to speed drug development and guide treatment decisions earlier.

 In both single-patient clinical trials, clinicians worked closely with scientific researchers in industry to drive the research forward with rapid intra-patient, pharmacokinetic-guided dose escalations to provide clinical treatment options for these patients.

We propose that window of opportunity clinical trials can be used for a more rapid translation of basic science discovery into the clinic with pharmacodynamic and biomarker analysis in the common treatment-naïve tumor tissue.6 Since window studies are traditionally conducted before surgical resection, most patients undergoing the initial diagnostic/ research biopsy have not been exposed to systemic chemo- therapy or cancer-related treatment. The research specimen obtained at the time of surgical resection not only provides a significantly larger amount of tissue for biomarker analysis, but the timing of treatment before surgery offers
the purest evaluation of changes in the tumor after the window treatment.

A more complicated version of a window of opportunity clinical trial design can also occur in the metastatic setting by layering individual agents and using novel sequences of therapeutic drugs and treatments. Incorporating research biopsies at rationally selected intervals offers biomarker analysis with single, double, and possible triple therapy at each time point. This creates a simple but sophisticated layering of therapeutics with associated biopsies for mechanistic analysis. Clinical trials with a lead-in window of a single agent offer this window before a planned combination therapy. At our institution, we have used window of opportunity clinical trials for patients with head and neck cancer in two settings: as a treatment before surgical resection and in the metastatic setting where patients are undergoing palliative radiation therapy with systemic chemotherapy.

In the surgical setting, Wheeler’s preclinical data indicated that overexpression of the recep- tor tyrosine kinase AXL is tightly linked to cetuximab resistance.

 In the previous window of opportunity trial, we employed two weeks of cetuximab (Erbitux) treatment before surgical resection to evaluate changes in Ki67 expression and gauge whether expression of AXL could serve as a predictive biomarker in cetuximab resistance (NCT03769311). Further preclinical data from our team suggested that tumors resistant to cetuximab had elevated AXL and AXL was responsible, in part, for the activation of the kinase c-Abl.

 Combination therapy of cetuximab plus imatinib (Gleevec) led to complete tumor regression without recurrence in animal models. To test this newly discovered combination in head and neck cancer we developed a surgical window of opportunity trial to test the combination by looking at Ki67 expression as a surrogate for proliferation (Figure 1).

In our clinical trial evaluating INCB081776, pembrolizumab (Keytruda), and palliative radi- ation therapy in patients with metastatic head and neck cancer (Figure 2), patients undergo a baseline biopsy followed by 14 days of treatment with INCB081776. A second research biopsy is obtained after completion of INCB081776 treatment, but before the addition of pembrolizumab monotherapy. Subsequently, patients
are treated with palliative radiation therapy for metastatic disease to alter the tumor microenvironment and stimulate the immune system. A third optional biopsy may be obtained for additional biomarker analysis. Patients will continue to receive combination therapy with INCB081776 plus pembrolizumab until disease progression or unacceptable toxicity. In this design, our team endeavored to provide a mechanism for obtaining tissue specimens to be analyzed in real time during the clinical trial, which would provide ongoing proof of concept. In addition, having biospecimens available for analysis during therapy can help refine and correlate toxicities and provide an early look at potential treatment changes.

We acknowledge that the traditional design of window trials may not provide an immediate effect for patients. Still, the data generated paves the way to refine treatment strategies for future cohorts and the next generation of clinical trials. As clinicians, we are obligated
to patients to be good stewards of research specimens provided to spur additional clinical research. We must engage with our scientific partners for close collaborations for real-time analysis to efficiently refine our scientific questions to speed the drug development process and ultimately improve the survival of patients with cancer. As part of the University of Wisconsin Head and Neck Specialized Program of Research Excellence grant, our work continues to improve upon this, focusing on horizontal and vertical collaborations to ensure that all cancer patients benefit.

This project was supported by the Specialized Program of Research Excellence program, through the National Institutes of Health (NIH) National Institute for Dental and Craniofacial Research and National Cancer Institute grants P50DE026787, P50CA278595, and R01CA262292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Figures were created with Biorender.com

Oncology Live®

Drug development is a difficult and ever-changing process, with new agents being developed by industry and academic partners.

Window of Opportunity Trials Are Needed for Novel Tissue Biomarker Analysis in Head and Neck Cancers

Expression of DLL3, an inhibitor ligand of the Notch pathway associated with tumorigenesis, has emerged as a target of interest for drug development.

Its involvement in the Notch pathway has been observed in small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors, with recent data also showing expression in melanoma, small cell bladder cancer, metastatic castration-resistant prostate cancer, glioblastoma multiforme, and neuroendocrine lung tumors.

“SCLC and other neuroendocrine carcinomas [NECs] are an area of great unmet clinical need,” Martin Wermke, MD, said in an interview with OncologyLive. “We have an established first-line treatment, which induces remissions; however, these remissions are usually shortlived and [if] patients relapse, [they] receive another chemotherapy with a lower response rate [and shorter] duration of response [DOR], and quickly run out of therapeutic options. It was discovered that NECs express DLL3 on their surface. This molecule is virtually absent from any other adult human tissue, so it’s an [ideal] target for immunotherapeutics.”

Targeted therapies in development leveraging DLL3 include antibody-drug conjugates (ADCs), CAR T-cell therapies, and bispecific T-cell engagers (BiTEs); however, recent trials have shown that T-cell engagers are currently the most promising.

 DLL3 is expressed on the surface of up to 85% of SCLC tumors and its expression varies across other tumor types as well sparking interest in the development of DLL3-targeting agents for patients with SCLC.

Wermke, who is head of the Early Clinical Trial Unit of the National Center for Tumor Diseases Dresden at the University Hospital Carl Gustav Carus in Germany, added, “[Because] DLL3 is expressed on the surface of the tumor cells but not on the surface of healthy tissue, you have the chance to redirect the T cells exactly where you want them to act. It’s relatively stably expressed, so this is not a problem of downregulation [where] you lose the antigen [as] the tumor evolves. It’s a stable target for different lines of treatment and that also differentiates it from other targets in SCLC.”

Early Data Emerges For the Novel Agent BI 764532

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Wermke presented data from a phase 1 study (NCT04429087) evaluating the T-cell engager BI 764532. The findings demonstrated a clinically acceptable safety profile and early efficacy when the agent was administered at doses of 90 μg/kg or greater in patients with DLL3-positive SCLC or NECs, groups that historically do not have many efficacious treatment options.

At doses of 90 μg/kg or more, BI 764532 elicited a partial response (PR) rate of 25% in the overall population (n = 71), 26% in the SCLC group (n = 39), 19% in those with extrapulmonary NECs (n = 27), and 60% in patients with large cell NECs (n = 5). Wermke noted that although the median DOR had not been reached, responses appeared to be durable, with a disease control rate of 52% for all patients given 90 μg/kg or more.

Furthermore, drug discontinuation due to treatment-related adverse effects (TRAEs) was low. Dose-limiting toxicities (DLTs) occurred
in 5 of 107 patients treated on the study at all dose levels but were reversible and patients recovered. T

3/4 cytokine release syndrome (CRS) occurring in 2 patients, as well as grade 3 confused state, grade 2 infusion-related reaction, and a grade 3 nervous system disorder occurring in 1 patient each.

“BI 764532 is a molecule that binds to DLL3 on the tumor cells and to CD3 on the T cells, thereby redirecting T cells to the tumor, inducing an immune cytologic cell death to the tumor cell. The next steps are for dose optimization,” Wermke said. “We will try to find a schedule [that] is convenient for smaller hospitals and private practice oncology [clinics] and will try to move this compound to earlier lines of treatment, combining it with first-line chemotherapy [as well as] standard maintenance regimens, and finding novel combinations with other
immunotherapeutics.”

“Focusing on the potentially efficacious dose levels above 90 μg/kg, the response rate was 25%, and these responses [did] not seem to be restricted to any of the subentities included. It’s not just [patients with] SCLC, extrapulmonary NECs, [or] large cell NECs for lung [who responded to treatment]—it’s all 3 of them. The responses seem to be durable, too. At the time of the data cutoff, 14 out of 18 responses were
ongoing and we have patients responding for 1 year or more.”

CAR T-cell Therapy and ADC Therapy Fall Short Targeting DLL3

Although the T-cell engager BI 764532 showed promise targeting DLL3, the ADC rovalpituzumab tesirine, which initially exhibited encouraging data, failed to provide a benefit over placebo as maintenance therapy, leading to its discontinuation by manufacturer AbbVie in 2019.

Additionally, a phase 1 trial (NCT03392064) evaluating the CAR T-cell therapy AMG 119 has been suspended and there are no patients actively enrolled, but the trial potentially may resume.

However, the half-life BiTE tarlatamab (formerly AMG 757) demonstrated encouraging results regarding response durability and safety in patients with relapsed/refractory SCLC.

 In the phase 1 DeLLphi-300 study (NCT03319940), patients included in the interim efficacy analysis (n = 107) experienced a confirmed objective response rate of 23% (95% CI, 15.7%- 32.5%) with best confirmed responses including complete response (2%), PR (22%), stable disease (28%), progressive disease (8%), or could not be evaluated/no assessment (40%). The DOR was 12.3 months (95% CI, 6.6-14.9) and 51.4% of patients experienced disease control (95% CI, 41.5%-61.2%).

The maximum-tolerated dose (MTD) of tarlatamab was not reached in the trial and the highest dose of the agent evaluated was 100 mg with 0.003, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, and 30.0 mg also examined. DLTs occurred in 6 patients and chills, pyrexia, and neutropenia were experienced by 1 patient each, all of whom were treated with 100 mg of tarlatamab. Pneumonitis occurred in a patient who was last treated at the 0.3-mg dose. Increased alanine aminotransferase and CRS occurred
in 1 patient each treated at 1 mg, and encephalopathy occurred in 1 patient treated at the 10-mg dose level.

Grade 3 or higher TRAEs occurred in 30.0% of patients. CRS was a toxicity of interest and was the most common TRAE, occurring in 52% of patients at any grade and in 1 patient at grade 3. Neurologic events related to treatment occurred in 50% of patients at any grade and neutropenia related to treatment occurred in 16% of patients at any grade. Additional common TRAEs included pyrexia (37%), dysgeusia (22%), fatigue (22%), and nausea (20%).

T-Cell Engagers Remain Agents of Interest 

Furthermore, the trispecific T-cell engager HPN328, which was granted orphan drug designation in March 2022 by the FDA,

 is under evaluation as monotherapy or in combination with atezolizumab (Tecentriq) in a phase 1/2 trial (NCT04471727) that is currently enrolling patients with advanced cancers expressing DLL3.

Interim data presented on the agent at the 2022 ASCO Annual Meeting revealed that 39% of patients (n = 7/18) treated with HPN328 monotherapy experienced a reduction in the sum of their target lesion diameter. This included 5 patients with SCLC, 1 with neuroendocrine
prostate cancer, and 1 with thymic atypical carcinoid. One patient with SCLC also achieved a confirmed PR.

The MTD of HPN328 was not reached and no DLTs occurred in the trial. Grade 3 TRAEs occurred in 6% of patients and grade 1 or 2 CRS occurred in 22% of patients. Additionally, no patients discontinued the study treatment due to AEs.

“It’s an exciting time for an immuno-oncologist, seeing all these great compounds and making progress for our patients. It’s rewarding to see patients who [we] would otherwise lose in a matter of months living on [the BiTE BI 764532] drug for more than 1 year; that’s something that makes you feel great if you’re able to do that,” Wermke said.

DLL3-Targeting Agents Are Poised to Fill Unmet Needs in SCLC

Although renal cell carcinoma (RCC) remains a difficult-to-treat disease, with patients with clear cell histology experiencing a median overall survival (OS) of approximately 13 months and a 5-year OS rate of less than 10%,

 updated results from clinical trials examining emerging therapeutic strategies have spurred optimism. This has led to discussion about treatment sequencing and selection based on adverse effect (AE) profiles and efficacy among patient subgroups.

An estimated 431,288 new kidney cancer cases were diagnosed globally in 2020, with RCC accounting for approximately 90% of these instances. The 3 most common subtypes of RCC are clear cell RCC (70%), papillary RCC (10%-15%), and chromophobe RCC (5%).

“Clear cell RCC is a disease that happens predominantly to men in their 50s and 60s,” Brian I. Rini, MD, FASCO, said. “We see a lot of these
patients. They can present asymptomatically, incidentally, [and] with hematuria symptoms. The [treatment] landscape [for this population] has been immune-based doublets.”

®, expert clinicians in the field of kidney cancer highlighted updates from clinical trials evaluating frontline treatment options for patients with advanced clear cell RCC, therapeutic choices in the second line and beyond, and options for patients with non–clear cell RCC, presented during the 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023).

Optimizing Frontline Advanced ccRCC Treatment

In recent years, there have been multiple posi- tive trials in advanced clear cell RCC, providing several options for patients that can be selected based on safety profiles, efficacy in different subgroups, and other factors.

During ASCO 2023, investigators presented findings from the final prespecified OS analysis of the phase 3 CLEAR trial (NCT02811861).

CLEAR enrolled treatment-naïve patients with advanced RCC with a clear cell component and randomly assigned them to receive the multire- ceptor tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) in combination with PD-1 inhibitor pembrolizumab (Keytruda; n = 355) or sunitinib (Sutent; n = 357).

At a median follow-up of 49.8 months (range, 41.4-53.1), patients in the combination arm experienced a median OS of 53.7 months (95% CI, 48.7-not estimable [NE]) compared with 54.3 months (95% CI, 40.9-NE) at a median follow-up of 49.4 months (95% CI, 41.6- 52.8) in the sunitinib arm (HR, 0.79; 95% CI, 0.63-0.99; P = .0424). However, the 24- (80.4% vs 69.6%, respectively), 36- (66.4% vs 60.2%), and 48-month (55.9% vs 52.5%) OS rates all favored the combination arm, although the benefit was driven more by the intermediate- and poor-
risk (HR, 0.74; 95% CI, 0.57-0.96) subgroup than the favorable-risk (HR, 0.94; 95% CI, 0.58-1.52) subgroup (Table 1)

Additionally, lenvatinib plus pembrolizumab provided a significant benefit in terms of progression-free survival (PFS), at 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0), respectively (HR, 0.47; 95% CI, 0.38- 0.57; P < .0001), and overall response rate (ORR), at 71.3% (95% CI, 66.6%-76.0%) vs 36.7% (95% CI, 31.7%-41.7%), respectively (relative risk, 1.94; 95% CI, 1.67-2.26; P < .0001).

Safety results from CLEAR showed that any-grade treatment-related AEs (TRAEs) occurred in 96.9% and 92.1% of patients in the combination and monotherapy arms, respectively. Grade 3 or higher TRAEs were reported
in both arms (74.1% vs 60.3%, respectively) as were deaths (1.1% vs 0.3%). The most common any-grade TRAEs in the investigational arm were diarrhea (56.0%), hypertension (54.3%), hypothy- roidism (44.9%), and decreased appetite (35.5%).

In another phase 3 trial, KEYNOTE-426 (NCT02853331), the safety and efficacy of pembrolizumab plus another TKI, axitinib (Inlyta), were compared with those of sunitinib in patients with treatment-naïve locally advanced or metastatic clear cell RCC. Findings from the 5-year analysis of KEYNOTE-426 presented during ASCO 2023 demonstrated that at a median follow-up of 67.2 months (range, 60.0-75.0), the median PFS was 15.7 months (95% CI, 13.6-20.2) in the combination arm (n = 432) compared with 11.1 months (95% CI, 8.9-12.5) in the sunitinib arm (n = 429; HR, 0.69; 95% CI, 0.59-0.81). The ORR was 60.6% with an 11.6% complete response (CR) rate compared with an ORR of 39.6% with a 4.0% CR rate, respectively. The median OS was 47.2 months (95% CI, 43.6-54.8) vs 40.8 months (95% CI, 34.3-47.5) in the respective arms (HR, 0.84; 95% CI, 0.71-0.99). When stratified by International Metastatic RCC Database Consortium risk score, patients with intermediate- and poor-risk disease (HR, 0.76; 95% CI, 0.62-0.93) appeared to derive more benefit than those with favorable risk (HR, 1.10; 95% CI, 0.79-1.54); (TABLE 2).

“We have many options at this indication,” Bruno R. Bastos, MD, said. “These data just corroborate that those regimens are effective regimens that can be used up front—the combination of VEGF TKIs and immunotherapies. It gives us more confidence that we are providing good care to our patients. However, this OS may make us think about perhaps the second- and third- line therapies that are coming along.”

“I divide it up between favorable risk, intermediate [risk], and...poor [risk],” Eric Jonasch, MD, added. “Within the intermediate- and poor[- risk category], [this comprises] those who have threatening disease vs non-threatening disease. [In] the favorable[-risk subgroup], I’ll typically use axitinib plus pembrolizumab. In the intermediate- and poor[-risk patients], if they have non-threatening disease, I’ll use ipilimumab [Yervoy] plus nivolumab [Opdivo], and then I’ll use either cabozantinib [Cabometyx] plus nivolumab or lenvatinib plus pembrolizumab in those who have life-threatening disease.”

Additionally, triplet regimens are showing promise in the frontline treatment of patients with advanced clear cell RCC. Findings from the phase 3 COSMIC-313 trial (NCT03937219) showed that patients who received cabozantinib in addition to nivolumab and ipilimumab (n = 276) did not reach the median PFS (95% CI, 14.0-not reached [NR]) vs a median PFS of 11.3 months (95% CI, 7.7-18.2) among patients who received placebo in place of cabozantinib (n = 274). The 12-month PFS rates were 57% (95% CI, 50%-63%) compared with 49% (95% CI, 42%-55%), respectively (HR, 0.73; 95% CI, 0.57-0.94; P = .01). However, findings from the prespecified subgroup analysis suggested that patients with poor-risk disease did not benefit from the addition of cabozantinib (HR, 1.04; 95% CI, 0.65-1.69).5

Safety findings showed that all patients in the investigational (n = 426) and control (n = 424) arms experienced an any-grade AE. The most common any-grade AEs in the experimental arm were diarrhea (50%) and increased alanine aminotransferase (49%) and aspartate amino-transferase (46%) levels.

Moreover, in the phase 3 MK-6482-012 trial (NCT04736706) investigators are planning to compare the safety and efficacy of the combination of pembrolizumab plus hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (Welireg) and lenvatinib or pembrolizumab/quavonlimab plus lenvatinib with those of pembrolizumab plus lenvatinib. The trial is currently recruiting patients with clear cell RCC who have not previously received systemic therapy for their disease. The coprimary end points are PFS and OS. Secondary end points include ORR, duration of response, and safety.

Novel combinations are also being examined in the second-line setting. In the phase 1/2 LITESPARK-024 trial (NCT05468697), investigators are evaluating belzutifan with or without the CDK4/6 inhibitor palbociclib (Ibrance).

In a preclinical study, the effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition, providing the clinical rationale for the trial. The open-label, randomized study is currently recruiting patients.

Regarding triplets, the phase 3 CONTACT-03 trial (NCT04338269) was
the first randomized phase 3 trial to examine the effect of adding an immune checkpoint inhibitor to a control arm. Updated findings presented at ASCO 2023 showed that patients with metastatic clear cell RCC who progressed on or after immune checkpoint inhibitor treatment did not experience a benefit with this approach.

Patients who received atezolizumab (Tecentriq) plus cabozantinib (n=263) experienced a median PFS of 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) among patients who were treated with cabozantinib monotherapy (n = 259; HR, 1.03; 95% CI, 0.83-1.28; P = .7844). Additionally, the median OS was 25.7 months (95% CI, 21.5-NE) vs NE (95% CI, 21.1-NE), respectively (HR, 0.94; 95% CI, 0.70- 1.27; P = .6902).

“Unfortunately, [CONTACT-03] was a nega- tive trial,” Rini commented. “Not surprisingly, there was an excess of toxicity in the combination arm. There was a difference [in excess of] 10% in high-grade AEs and serious AEs between the combination arm and the monotherapy arm, with 3 deaths due to toxicity in the combination arm. So, not only was it not as efficacious, but it was also more toxic.”


Elizabeth Plimack, MD, MS, argued that she “wouldn’t throw out this entire approach for all patients based on this study. If we looked at patients who responded and then progressed or patients who had a gap or a stronger combination, we might do better.” However, she acknowledged that this approach should not be used in clinical practice until more data proving its benefit are available.

Despite the disappointing findings from CONTACT-03, findings from the phase 1/2 KEYMAKER-U03B/ MK-3475-03B trial (NCT04626518), also presented during ASCO 2023, displayed more favorable data for patients with clear cell RCC. Results showed that the combination of belzutifan and lenvatinib showed promising antitumor activity in patients with clear cell RCC who experienced disease progression on or after treatment with PD-1/L1 inhibitors and VEGF TKIs. Efficacy-evaluable patients (n = 32) experienced a median PFS of 11.2 months (95% CI, 4.2-NR), with a 6-month PFS rate of 55%. Among 24 patients who underwent at least 2 postbaseline scans, the ORR was 50% (95% CI, 29%-71%); all responses were partial.

The combination of belzutifan and lenvatinib is now under further eval- uation in the phase 3 LITESPARK-011 study (NCT04586231).

Non–clear cell RCC comprises a group of subtypes that differ genetically and biologically from each other and are extremely rare. There is no current standard of care for these rare forms of non–clear cell RCC and the prognosis for these patients is generally poor.

 However, during ASCO 2023, promising findings were presented from a pair of phase 2 clinical trials in this population.

Updated findings from the phase 2 KEYNOTE-B61 trial (NCT04704219) revealed that lenvatinib plus pembrolizumab showed antitumor activity in patients with treatment- naïve non–clear cell RCC; the ORR was 49% (95% CI, 41%-57%), with a 6% CR rate, in the efficacy-evaluable population (n = 158). Moreover, the median PFS was 17.9 months (95% CI, 14.0-NR) and the median OS was NR (95% CI, NR-NR). The 1-year PFS and OS rates were 63% (95% CI, 54%-70%) and 82% (95% CI, 75%-88%), respectively.

To date, KEYNOTE-B61 is the largest prospective trial evaluating an immune checkpoint inhibitor combination in non–clear cell RCC. Investigators concluded that the findings presented at the 2023 ASCO Annual Meeting supported the use of pembrolizumab plus lenvatinib as a frontline treatment option for patients with non–clear cell RCC, irrespective of histology. Patients with papillary (n = 93), chromophobe (n = 29), unclassified (n = 21), translocation (n = 6), and other (n = 9) histologies experi- enced ORRs of 54.0%, 28.0%, 52.0%, 67.0%, and 56.0%, respectively.

Additionally, investigators also presented findings from a phase 2 trial (NCT03635892) that evaluated the combination of cabozantinib plus nivolumab in patients with metastatic non–clear cell RCC. At a median follow-up of 34 months (range, 20-51), the median OS was 28 months (95% CI, 23-43) and the median PFS was 13 months (95% CI, 7-16) among 40 efficacy-evaluable patients. Additionally, the 18- and 36-month OS rates were 70% (95% CI, 53%-82%) and 44% (95% CI, 28%-60%), respectively.

Findings from both studies indicated that the safety profiles of the 2 combinations were in-line with their previously observed AE profiles. In KEYNOTE-B61, most patients experienced an AE (94.3%), with hypertension (57.0%), diarrhea (43.7%), and hypothyroidism (36.7%) being the most common. In the latter phase 2 study, the most common any-grade AEs were fatigue (70%), palmar-plantar erythrodysesthesia syndrome (68%), and diarrhea (63%).

“If we take a step back from all these data, it’s kind of amazing how many [patients] are living beyond 5 years,” Plimack said in conclusion. “We could not have imagined this when we started these studies. I’m excited to see [where this research goes] and as we cross-compare and decide which [approach] is better, [we have to acknowledge] they’re all really great compared with where we were before.”

Padala SA, Kallam A. Clear cell renal carcinoma. In: StatPearls. StatPearls Publishing; 2023. Updated May 22, 2023. Accessed September 18, 2023. https://www.ncbi.nlm.nih.gov/books/ NBK557644/

Bukavina L, Bensalah K, Bray F, et al. Epidemiology of renal cell carcinoma: 2022 update. 

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Motzer RJ, Porta C, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). 

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Rini BI, Pilmack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. 

. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl. LBA4501

Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. 

. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851

Choueiri TK, Plimack ER, Powles T, et al. Phase 3 study of first-
line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab
+ lenvatinib for advanced renal cell carcinoma (RCC). 

. 2022;40(suppl 6):TPS399. doi:10.1200/JCO.2022.40.6_suppl.TPS399

McDermott DF, Peer A, Agarwal N, et al. LITESPARK-024: randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma (RCC). J Clin Oncol. 2023;41(suppl 16):TPS4603. doi:10.1200/JCO.2023.41.16_suppl.TPS4603

Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone
after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. 

. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500

Albiges L, Beckermann K, Miller WH, et al. Belzutifan plus lenvatinib for patients (pts) with advanced clear cell renal cell carcinoma (ccRCC) after progression on a PD-1/L1 and VEGF inhibitor: preliminary results of arm B5 of the phase 1/2 KEYMAKER-U03B study. 

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10. Sepe P, Ottini A, Pircher CC, et al. Characteristics and treatment challenges of non-clear cell renal cell carcinoma. 

. 2021;13(15):3807. doi:10.3390/cancers13153807

Lee CH, Gurney H, Atduev V, et al. First-line lenvatinib + pembrolizumab treatment across non-clear cell renal cell carcinomas: results of the phase 2 KEYNOTE-B61 study. 

. 2023;41(suppl 16):4518. doi:10.1200/JCO.2023.41.16_suppl.4518

Lee CH, Fitzgerald KN, Voss MH, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: updated
results from a phase 2 trial. 

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Although renal cell carcinoma remains a difficult-to-treat disease, with patients with clear cell histology experiencing a median overall survival of approximately 13 months and a 5-year overall survival rate of less than 10%, updated results from clinical trials examining emerging therapeutic strategies have spurred optimism.

New Data Bring Excitement, Raise Questions in Advanced RCC

This article highlights the rather profound fiscal implications of the combined effect of 2 quite different but closely related components of the rapidly evolving cancer treatment paradigm. The first element is the recognition that it is appropriate to consider the clinical courses of several advanced malignancies as being serious, life-threatening, and frequently fatal. However, these can also be characterized more as 

. The second is the increasing success of the efforts made by the pharmaceutical/biotech industry to develop antineoplastic therapeutics that extend survival timelines.

To begin this discussion, it is appropriate to acknowledge just how substantially clinical care in most (but certainly not all) malignancies has evolved over the past several decades. It was not that long ago when patients with what appeared to be localized or regional-only advanced solid tumors would be seen by a surgeon for resection of the lesion (if possible), perhaps followed by external beam radiation to the involved regions to enhance the opportunity for local disease control, and in a few settings (eg, breast cancer) management might include 4 to 6 total cycles of an adjuvant chemotherapy regimen every 3 to 4 weeks. If the cancer should recur or be metastatic at presentation, systemic chemotherapy might have been administered as a primary therapeutic modality, but again with a few notable exceptions (eg, lymphomas, ovarian cancer), its effectiveness was quite modest, with considerable risks for short-term distressing (eg, emesis, fatigue, stomatitis) or even fatal (eg, neutropenic sepsis, severe kidney, or cardiac dysfunction) toxicities.

In addition, even when a measurable (eg, imaging, tumor marker) or symptomatic (eg, reduction in cancer-associated pain) response was observed, in most patients such favorable developments lasted for only a few months, if not a shorter duration. Further, second-line antineoplastic drug options were even less clinically useful.

, with the critical exception of certain hormonal strategies (eg, those used in managing breast cancer), was appropriately not a routine component of the oncologist’s armamentarium. For patients who experienced a response to a treatment regimen (objective, subjective, or both), prolonged continuation of treatment would almost certainly result in persistence or worsening of any adverse effects already experienced (eg, emesis with each treatment cycle, persistent hair loss) or the potential development of treatment-associated cumulative toxicities (eg, peripheral neuropathy, congestive heart failure, acute leukemia). And most relevant, phase 3 trial data supporting the survival benefits of extending treatments were lacking.

Fast forward to today. We regularly learn of phase 3 trial data that reveal the favorable survival effect of a variety of maintenance approaches to cancer management (eg, bevacizumab [Avastin] and PARP inhibitors in ovarian cancer) and the effectiveness of second-line or later treatments following disease progression after primary therapy (eg, checkpoint inhibitors in several disease settings). Further, published population-based data have confirmed the real-world impact of both early detection strategies and evolving cancer treatments on cancer-associated survival.

 For example, earlier in 2023 the American Cancer Society reported a 33% overall reduction (“3.8 million deaths averted”) in cancer deaths from 1991.

Before pivoting to briefly discuss the second issue previously highlighted, that of the current antineoplastic drug development paradigm, it is relevant to note that although the successful sequential administration of antineoplastic drugs over an extended period of time (increasingly measured in 

) permits an increasing proportion of individuals to experience extended survival with a satisfactory quality of life (defined by the patient), it is uncertain if government officials, health care policy makers, third-party payers, employers, clinicians, researchers, and individual patients fully appreciate the implications of this continually evolving process.

One wonders, for instance, how many patients and families would initially approach a new diagnosis of an advanced cancer with the mindset that although current therapeutic strategies may not cure the malignancy, an acceptable alternative to achieving this goal would be the possibility of prolonged sequential delivery of a variety of strategies. This may include therapies directed by tumor and liquid biopsy genomic analyses, results of imaging studies, and patient symptoms. Success in this clinical scenario would be determined by the ability to keep the cancer from progressing for an extended period with the individual able to lead a relatively normal life.

One also wonders if those involved in treatment decision-making understand that a single patented agent or combination drug regimens that might be delivered over this extended period can cost $100,000 or more per year, a figure likely to continue to rapidly rise with the passage of time.

This is not to minimize the truly remarkable contributions of individual researchers, academic teams, and numerous pharmaceutical and biotech companies that are part of the remarkable progress in both the revolutionary changes in our understanding of cancer biology and the subsequent development of beneficial novel agents. Although it is theoretically possible that the delivery of a single dose of an agent (eg, chimeric antigen receptor T-cell therapy) may result in a curative outcome, that scenario is not what is currently observed in the existing paradigm of drug treatment of advanced cancers.

The intent in writing this commentary has been to encourage an open societal discussion to encourage ideas to pursue a rational way forward, to acknowledge our evolving understanding of the remarkable complexity of individual cancer biology, to ensure continued strong pharmaceutical/biotech industry support for the development of novel therapeutics based on this biology, and to recognize the 

cost of required long-term treatments with increasingly expensive therapeutics

Regardless of what one might wish to believe, the current oncology-associated drug cost trajectory is simply not sustainable. It is notable that a recently published lay press book has challenged the existing scientific focus on precision cancer medicine.

 The text critically highlights alternative funding with an emphasis on environmental factors associated with disease development (eg, obesity, pollution, smoking, alcohol, social determinants, etc).

 The book also includes, in some detail, the absence of meaningful economic incentives for manufacturers to lower cancer drug costs, despite the more chronic nature of the disease processes, bolstered by the opportunity for financial rewards resulting from the extended delivery times.

In conclusion, for the benefit of all current and future patients with cancer, it is essential that rational solutions to this dilemma be proposed, objectively evaluated, and ultimately implemented.

Maurie Markman, MD, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer Statistics, 2023. 

. 2023;73(1):17-48. doi:10.3322/caac.21763

Tyranny of the Gene: Personalized Medicine and Its Threat to Public Health

Maurie Markman, MD, highlights the rather profound fiscal implications of the combined effect of 2 quite different but closely related components of the rapidly evolving cancer treatment paradigm. 

Vol. 24/No. 16 | Oncology Live®

Data Reveal Medicaid Expansion May Result in Mortality Rate Reductions for Patients With Cancer

Window of Opportunity Trials Are Needed for Novel Tissue Biomarker Analysis in Head and Neck Cancers

DLL3-Targeting Agents Are Poised to Fill Unmet Needs in SCLC

New Data Bring Excitement, Raise Questions in Advanced RCC

The Bleak Fiscal Implications of Advanced Cancer as a Chronic Illness