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Investigators hope that first-in-class agents will combat dysfunction of the Hippo pathway, which promotes YAP and TAZ activation resulting in uncontrolled proliferation and impaired differentiation, by inhibiting the transcription function of TEAD-YAP.

“Perhaps the most recognizable component of the Hippo pathway is the gene NF2 that encodes the protein Merlin. When the pathway is on or intact, YAP and TAZ are sequestered or stuck in the cytoplasm where they’re degraded,” Ibiayi Dagogo-Jack, MD, explained in an interview with OncologyLive. “When the pathway is abnormal, YAP and TAZ are not phosphorylated— they’re free to go to the nucleus where they bind to TEAD transcription factors, and this leads to transcription of genes that promote survival [and] impaired differentiation.”

A first-in-human phase 1 clinical trial (NCT04665206) is evaluating the agent VT3989 in patients with advanced solid tumors and the trial is enriched for those with mesothelioma. It is also enriched for patients with NF2 mutations, which are common in mesothelioma and are one mechanism by which Hippo pathway control of YAP and TAZ is inactivated in tumors

—the inactivation of NF2 can contribute to dysregulation of the Hippo pathway.

Dagogo-Jack, an assistant professor of medicine at Harvard Medical School and a thoracic oncologist at Massachusetts General Hospital, both in Boston, noted that “approximately 60% of mesotheliomas have some sort of dysregulation of the Hippo pathway.”

Additionally, investigators of the study explained that palmitoylation of a conserved cysteine is required for the binding of TEAD to YAP/TAZ; the palmitate is buried in a central pocket in the YAP-binding domain of TEAD.1 “VT3989 binds to a palmitoylation pocket that is used by TEAD transcription factors to bind to YAP and TAZ,” Dagogo-Jack said. “It inhibits that binding and then hopefully you subdue or suppress that transcription that is vital for cancer cell survival.”

Early Efficacy Signals When Targeting HIPPO-YAP-TEAD 

Data presented at the 2023 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer revealed that VT3989 demonstrated antitumor activity inhibiting the Hippo pathway and activity was durable in patients with advanced mesothelioma regardless of NF2 mutation status.

“We always have to be careful when we’re looking at first-in-human studies because you get a variety of dose levels, and we’re trying to see a signal as far as the safety, but also we’re encouraged when we see some patients with partial responses [PRs],” Dagogo-Jack said.

As of July 31, 2023, among patients with mesothelioma from a total of 5 cohorts (n = 44), 3 patients achieved a PR and were continuing treatment, 1 patient achieved a PR and completed treatment, and 2 patients experienced a PR followed by disease progression. Additionally, 4 patients who achieved stable disease (SD) were continuing treatment and 7 patients who experienced SD had completed treatment.

Data presented at the 2023 American Association for Cancer Research Annual Meeting from the study demonstrated that of 69 patients enrolled with advanced solid tumors primarily consisting of mesothelioma, 7 patients with measurable disease had a response per RECIST 1.1 criteria and 34 patients with measurable disease had a best response of SD. Responses were seen among patients with and without NF2 mutations.

“We’ve seen 7 PRs [and] most of these, all but 1, are in mesothelioma,” Dagogo-Jack noted. “I’ve been using mesothelioma as a broad term, but there [are patients with] pleural, peritoneal, and pericardial mesothelioma who are enrolled in this study. Interestingly, in those rare types of mesotheliomas we’ve been seeing the PRs.”

“The other key thing is that although we would love to have a response, response assessment is a bit more challenging to do in mesothelioma based on how the disease grows and so SD is also something that we’re happy with if the drug is not toxic. Some durable SD has been seen as well—approximately 30 of the 50-plus patients presented had SD. The final important point on the efficacy is we’ve seen some quite durable responses,” Dagogo-Jack said.

VT3989 was administered in a 3 plus 3 dose escalation design with a dose expansion. The agent was given continuously at 25-, 50-, 100-, 150-, and 200-mg daily in cohorts 1 to 5 (n = 27). Intermittent dosing schedules were subsequently evaluated in cohorts 6 to 10 (n = 42) with patients receiving 200 mg for 2 weeks on/1 week off, 200 mg for 1 week on/2 weeks off, 200 mg for 2 weeks on/2 weeks off, 100 mg for 2 weeks on/2 weeks off, and 150 mg for 1 week on/3 weeks off. VT3989 was administered at 100 mg in cohort 11 and 50 mg in cohort 12, both for 15 days continuously, then weekly on days 1, 8, and 15. No dose-limiting toxicities were observed in any of the 12 cohorts.

“We have seen with this drug, because [investigators] monitor it very closely, that people do leak albumin in the urine and that has led to dose interruptions. It’s one of the reasons that they’re investigating and exploring a variety of dosing schedules, in particular interrupted dosing schedules, to try to maximize the efficacy while sparing any kind of nephrotoxicity,” Dagogo-Jack said. 

Grade 1 to 3 albuminuria occurred in 53.5% of patients on the study, with 4.3% of patients experiencing the toxicity at grade 3. No grade 4 events were reported, and all albuminuria and proteinuria events recorded so far were reversible regardless of doses and schedules received.

Investigators noted that when VT3989 was administered at a dose of 100 mg or less intermittently, there were less frequent and less severe cases of albuminuria. The median urine albumin-creatinine ratio was 341.9 mg/gm (range, 17.0-2715.4) in patients who received VT3989 at 25 to 200 mg daily continuously or 150 to 200 mg on 4 intermittent dosing schedules (cohorts 1-8 and 10; n = 50) compared with 60.4 mg/gm (range, 7.55-431.2) in those who received the agent at 50 to 100 mg on 2 intermittent dosing schedules (cohorts 9, 11, and 12; n = 19).

"This drug is a little different; it’s an oral drug, so a bit of a departure from our traditional intravenous therapies that we use as far as our chemotherapies with mesothelioma. The integrity of the podocytes or the kidney filtration system is impacted by this drug and one of the key things that people are watching out for is whether it causes nephrotic syndrome,” Dagogo-Jack said. 

The most common grade 1 to 3 adverse effects (AEs) aside from albuminuria included peripheral edema (36.2%), fatigue (24.6%), nausea (20.3%), increased alanine aminotransaminase (11.6%), increased aspartate aminotransaminase (11.6%), increased cholesterol (7.2%), anorexia (7.2%), hyperlipidemia (7.2%), and periorbital edema (7.2%). No grade 5 AEs occurred in the trial.

Moreover, VT3989 gives dose-proportional exposure following administration and the half-life of the agent is approximately 12 to 15 days—pharmacodynamic exposure on day 15 is approximately 7 times that on day 1. Due to the agent’s long half-life, Dagogo-Jack explained that “patients may need to hold the drug for quite a bit before their levels come to a level where you can resume dosing the drug.”

“Preclinically when [investigators] looked at mesothelioma disease models and tried to predict who might benefit from treatment and were thinking about [whether the trial] should be restricted to patients with NF2 mutations, it did seem that having an NF2 mutation may have correlated with a greater antiproliferative effect of the drug,” Dagogo-Jack explained. “But that really hasn’t been the case clinically. We must have a bit of pause in terms of interpreting the clinical data because not everyone had NF2 mutation testing when they joined the study and there’s a large chunk of patients where NF2 [status] is unknown.”

Of the 69 patients enrolled in cohorts 1 through 12 of the trial, 37 had NF2 mutations including somatic (n = 31) and germline (n = 6). NF2 mutation status was unknown for 19 patients and 13 patients had NF2 wild-type disease.

“Perhaps the greatest area for this drug is in mesothelioma [as] this is a rare disease. There are only 2 approved therapies, their initial approvals are in the first-line setting, and we don’t have anything approved after these drugs,” Dagogo-Jack explained, as nivolumab (Opdivo) and ipilimumab (Yervoy) are currently approved for first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

 “There are a couple of chemotherapies we turn to, and there is incredible need for more therapies and particularly more precise therapies for this patient population.” 

Additionally, dose-optimization expansion cohorts are under way and are evaluating different schedules as well as doses of VT3989 in 2-stage designs. Investigators also revealed at IASLC that a multivariate analysis is under way and will explore potential predictors of nephropathy.

“The hope is that a drug like VT3989, if with further study there’s good efficacy and a reasonable safety profile, [could] with future testing make its way into the therapeutic arsenal for mesothelioma,” Dagogo-Jack said. “But we still have work to do and future studies we need to do to learn more about this drug in larger cohorts and to figure out what is the right way to give the drug in terms of the dosing and the dosing schedule.”

Yap TA, Kwiatkowski DJ, Desai J, et al. First-in-class, first-inhuman phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis (NF2) mutations. Cancer Res. 2023;83(suppl 8):CT006. doi:10.1158/1538-7445.AM2023-CT006

Yap TA, Desai J, Dagogo-Jack I, et al. First-in-human phase 1 trial of VT3989, a first-in-class YAP/TEAD inhibitor in patients with advanced mesothelioma. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. P2.19-01.

Jablons D, Woodard G. Targeting the Hippo pathway. J Thorac Oncol. 2018;13(suppl 10):S306. doi:10.1016/j.jtho.2018.08.205

Luo J, Deng L, Zou H, et al. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res. 2023;42(1):130.doi:10.1186/s13046-023-02704-2

FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. FDA. October 2, 2020. Accessed November 8, 2023. bit.ly/47q2EW6

Articles

Investigators hope that first-in-class agents will combat dysfunction of the Hippo pathway by inhibiting the transcription function of TEAD-YAP.function of TEAD-YAP.

First-in-Class YAP/TEAD Inhibitor Demonstrates Early Efficacy Targeting Hippo Pathway

Renal cell carcinoma (RCC) accounted for approximately 90% of the estimated 431,288 new cases of kidney cancer that were diagnosed globally in 2020.

 Although multiple treatment options exist for patients with advanced disease, there remains an unmet need for additional regimens that offer greater efficacy and provide an option for patients in hard-to-treat subgroups, such as those with metastases or poor International Metastatic RCC Database Consortium (IMDC) risk status.

, expert oncologists who treat patients with advanced RCC discussed updates from clinical trials presented during the 2023 European Society for Medical Oncology (ESMO) Congress that further defined the treatment paradigm in advanced RCC and gave a peek into the potential future of the disease management.

Several regimens are available to clinicians to choose from for the frontline treatment of patients with advanced RCC and thus also have multiple factors to consider when selecting the most appropriate regimen. “IMDC [risk score] continues with every study to demonstrate its powerful prognostic capacity,” 

, said. “[However], there are some limitations you need to consider. Sites of metastasis are particularly important. Does the patient have an [inferior vena cava] thrombus? That’s not part of the IMDC risk factors and those patients have a particularly poor prognosis, so it’s important to consider the IMDC but, as a clinician in the room with the patient, [to also] consider these other factors.”

Clear Cell RCC Therapeutic Choices Take Steps Forward

During the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, results from the final prespecified overall survival (OS) analysis of the phase 3 CLEAR trial (NCT02811861) were presented. CLEAR enrolled treatment-naive patients with advanced RCC with a clear cell component and randomly assigned them in a 1:1 manner to be treated with either the multireceptor tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) plus the PD-1 inhibitor pembrolizumab (Keytruda; n = 355) or the TKI 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; 

 = .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.

Additionally, lenvatinib plus pembrolizumab provided a significant benefit in terms of progression-free survival (PFS) vs sunitinib 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; 

 < .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; 

“It’s remarkable sitting here today,” 

, said. “I started my clinic in 2015 and none of the regimens that we’re discussing were available. To have a regimen that has a median PFS of close to 2 years is quite remarkable. What we got to see over time is additional follow-up, which helps us with OS. The OS [HR] has increased with time and is now close to 0.8. There are a lot of challenges with using OS [to draw conclusions] on these trials where you have multiple later-line options, especially when we’re doing global studies where these options are very different between countries. One of the concerns that may be raised is when you start with such a potent regimen, your later-line options are not going to be as active.”

Safety results from CLEAR showed that any-grade treatment-related adverse effects (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%), hypothyroidism (44.9%), and decreased appetite (35.5%).

More recently, during the 2023 ESMO Congress, investigators presented findings from a post hoc analysis of CLEAR. The exploratory analysis evaluated the efficacy of lenvatinib plus pembrolizumab vs sunitinib based on patient baseline metastatic characteristics at the final prespecified OS analysis. Patients were stratified based on metastatic site (lung vs lymph node vs bone vs liver vs brain), number of metastatic sites (1 vs ≥ 2), and baseline sums of diameters of target lesions (≥ 60 mm vs < 60 mm).

At the July 31, 2022, data cutoff, lenvatinib plus pembrolizumab provided a benefit over sunitinib in terms of ORR in every subgroup that was examined. The greatest benefit with the combination was observed in patients with baseline sums of diameters of target legions of at least 60 mm (odds ratio [OR], 10.50; 95% CI, 6.08-18.13), baseline lung metastasis (OR, 5.19; 95% CI, 3.48-7.72), and at least 2 metastatic sites or organs (OR, 5.06; 95% CI, 3.40-7.53).

Similarly, the combination of lenvatinib plus pembrolizumab provided significant benefit in terms of PFS in every subgroup that was examined. The most pronounced benefit was observed in patients with baseline brain metastasis (HR, 0.32; 95% CI, 0.07-1.59), baseline sums of diameters of target lesions of at least 60 mm (HR, 0.39; 95% CI, 0.29-0.53), and at least 2 metastatic sites/organs (HR, 0.40; 95% CI, 0.31- 0.50; 

Updated findings from the 5-year analysis of the phase 3 KEYNOTE-426 trial (NCT02853331), which compared the TKI combination of axitinib (Inlyta) plus pembrolizumab with sunitinib in patients with treatment-naive locally advanced or metastatic clear cell RCC, were also presented during the 2023 ASCO Annual Meeting. At a median follow-up of 67.2 months (range, 60.0-75.0), results from KEYNOTE-426 demonstrated that 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.

Additionally, 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 combination arm vs the control arm, respectively (HR, 0.84; 95% CI, 0.71-0.99). When stratified by IMDC risk score, patients with intermediate- and poor-risk disease (HR, 0.76; 95% CI, 0.62-0.93) appeared to derive more benefit from treatment with the combination vs sunitinib than those with favorable risk (HR, 1.10; 95% CI, 0.79-1.54).

Another phase 3 study, CheckMate 9ER (NCT03141177), is testing a different checkpoint inhibitor combination in clear cell RCC, combining the PD-1 inhibitor nivolumab (Opdivo) with the multireceptor TKI cabozantinib (Cabometyx). The study enrolled patients with advanced clear cell RCC and randomly assigned them in a 1:1 manner to receive either the combination (n = 323) or sunitinib (n = 328).

Updated findings from the 3-year follow-up of CheckMate 9ER, which were presented during the 2023 ASCO Genitourinary Cancers Symposium, showed that at a median follow-up of 44.0 months and a minimum follow-up of 36.5 months, the median OS was 49.5 months vs 35.5 months in the combination and control arms, respectively (HR, 0.70; 95% CI 0.56- 0.87; 

 = .0014). Additionally, the median PFS was 16.6 months vs 8.4 months, respectively (HR, 0.59; 95% CI, 0.49-0.71; 

Notably, the combination arm was favored over the control arm in terms of response rate, median PFS, and median OS in nearly every IMDC risk score subgroup that was examined. The most pronounced PFS benefit with nivolumab plus cabozantinib vs sunitinib was observed in patients with IMDC poor-risk disease (HR, 0.37; 95% CI, 0.24-0.57), as was the most significant OS benefit (HR, 0.46; 95% CI, 0.30-0.72; 

“The combination of cabozantinib [plus] nivolumab is one of the most common combinations [in clinical practice]. I’ve been using it since it was approved a few years ago,” 

. “The OS continues to be quite strongly maintained with the combination compared with sunitinib. It’s so gratifying to see that median OS of our patients consistently exceeding 4 years. There was a very strong improvement in PFS, which continues to be maintained after almost 4 years of follow-up, with a 50% reduction in risk of progression [or death]. I continue to be very impressed by [these] data.”

KEYNOTE-B61 Aims to Add Option in Non–Clear Cell RCC

Beyond clear cell RCC, the combination of lenvatinib plus pembrolizumab has also shown antitumor activity among patients with treatment- naive advanced non–clear cell RCC. To date, the phase 2 KEYNOTE-B61 trial (NCT04704219) is the largest prospective trial evaluating an immune checkpoint inhibitor combination in non–clear cell RCC.

“Non–clear cell RCC is a heterogeneous bag of different diseases, with papillary RCC being the most common, but we also have translocation RCC, unclassified RCC, chromophobe RCC, and others,” 

, said. “The challenge is: How shall we treat them? These tumors don’t have the same biology. However, until a few years ago, we were treating them the same way. We have data supporting the use of VEGF TKIs. [However], with single-agent TKIs, the response rate is somewhere between 5% [and] 20%, and the [median] PFS is quite short—approximately 6 months.”

At the November 7, 2022, data cutoff, findings from KEYNOTE-B61, which were presented during the 2023 ASCO Annual Meeting and subsequently published in 

, revealed that efficacy-evaluable patients who received lenvatinib plus pembrolizumab (n = 158) achieved an ORR of 49% (95% CI, 41%-57%) with a 6% CR rate. The median PFS was 17.9 months (95% CI, 14.0-not reached [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.

Notably, the combination displayed antitumor activity regardless of RCC histology. Patients with papillary (n = 93), chromophobe (n = 29), unclassified (n = 21), translocation (n = 6), and other (n = 9) histologies experienced ORRs of 54% (95% CI, 43%-64%), 28% (95% CI, 13%-47%), 52% (95% CI, 30%-74%), 67% (95% CI, 22%-96%), and 56% (95% CI, 21%-86%), respectively.

In terms of safety, most patients experienced an any-grade AE (99.4%), 65.2% had an AE of grade 3 to 5 severity, and no patients died due to a TRAE. Treatment dose reductions (34.2%), interruptions (72.2%), and discontinuations (15.8%) due to AEs were all reported. The most common any-grade TRAEs consisted of hypertension (57.0%), diarrhea (43.7%), and hypothyroidism (36.7%).

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. The safety profile of the combination was manageable and consistent with what has been observed in previous studies of pembrolizumab plus lenvatinib, they added. KEYNOTE-B61 is still active but is not recruiting new patients.

“The key finding is that the response rate is reaching 50% in this challenging patient population, except for the chromophobe [RCC population], which was a bit lower in the range of 30%,” Albiges said. “The PFS is indeed prolonged with the combination regimen. [Median OS] was NR at the time of the data cutoff, but it’s likely to be above what we’ve had with other combinations in other trials in the past because, at the 1-year mark, 80% of patients were still alive. We are changing the game with combination therapy. Now, in my clinic, a patient [who] is not enrolled in a trial [and] has non–clear cell histology would be considered for combination therapy.”

After reviewing multiple case studies pertaining to the management of patients with advanced RCC, the panelists shifted focus to the future and opened their conversation by discussing emerging regimens under investigation in the space.

One regimen that is showing promise in underserved patients with IMDC intermediate- or poor-risk advanced RCC is the triplet combination comprising cabozantinib, nivolumab, and ipilimumab (Yervoy), which is being compared with placebo plus nivolumab and ipilimumab, in patients with clear cell disease in the phase 3 COSMIC-313 trial (NCT03937219). Data from the study, which were published in the 

, revealed that patients in the triplet arm (n = 276) achieved a median PFS of NR (95% CI, NR, 14.0-NE) vs 11.3 months (95% CI, 7.7-18.2) among patients in the placebo arm (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; 

Regarding safety, 100% of patients in both the investigational (n = 426) and control arms (n = 424) experienced an any-grade AE. The most common any-grade AEs in the experimental arm included diarrhea (50%), increased alanine aminotransferase levels (49%), and increased aspartate aminotransferase levels (46%). Grade 3 or 4 AEs in the triplet arm occurred at a rate of 79% and included increased alanine aminotransferase levels (27%), increased aspartate aminotransferase levels (20%), and hypertension (10%).

“Although COSMIC-313 was positive for the primary end point, the toxicity is just a little too much,” 

, said. “There were a lot of grade 3/4 toxicities, which probably are limiting, and not a lot of patients got the full 4 doses of ipilimumab. So right now, the recommendation is that triplet therapy is not ready for prime time yet.”

During the 2023 ESMO Congress, investigators presented updated findings from multiple clinical trials evaluating doublet regimens and monotherapy strategies in the frontline setting of advanced RCC. The panelists paid special attention to findings from the phase 3 LITESPARK-005 (NCT04195750) and RENOTORCH (NCT04394975) trials.

LITESPARK-005 enrolled patients with advanced clear cell RCC who had received previous treatment with 1 to 3 systemic regimens, including a PD-1/L1 inhibitor and a VEGFdirected TKI, and randomly assigned them 1:1 to receive either belzutifan (Welireg; n = 374) or everolimus (Afinitor; n = 372). At a median follow-up of 25.7 months (range, 16.8-39.1), the median PFS per RECIST v1.1 criteria in both arms was 5.6 months (HR, 0.74; 95% CI, 0.63-0.88); however, the 12- (33.7% vs 17.6%, respectively) and 18-month PFS rates (22.5% vs 9.0%) both favored belzutifan. Notably, the ORRs were 22.7% (95% CI, 18.6%-27.3%) vs 3.5% (95% CI, 1.9%-5.9%), respectively (

In RENOTORCH, investigators compared the safety and efficacy of toripalimab- tpzi (Loqtorzi) plus axitinib with that of sunitinib for the frontline treatment of patients with advanced RCC. At a median follow-up of 14.6 months, the median PFS in the combination arm (n = 210) was 18.0 months (95% CI, 15.0-NE) vs 9.8 months (95% CI, 8.3-13.8) in the sunitinib arm (n = 211; HR, 0.65; 95% CI, 0.49-0.86; 

 = .0028). The ORR was 56.7% with a 4.8% CR rate, vs 30.8% with a 3.8% CR rate, respectively.

“I am incredibly excited about how far we’ve come in terms of treatment, and I am excited that we have a lot of potential targets for cellular therapy that are under exploration,” Campbell said in conclusion.

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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Gruenwald V, McKay RR, Buchler T, et al. Tumor response by baseline metastases in patients (pts) with renal cell carcinoma (RCC) treated with lenvatinib (L) plus pembrolizumab (P) vs sunitinib (S): post hoc analysis of the CLEAR trial. 

. 2023;34(suppl 2):S1024-S1025. doi:10.1016/j.annonc.2023.09.1133

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

Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. 

. 2023;41(suppl 6):603. doi:10.1200/ JCO.2023.41.6_suppl.603

Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. 

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

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Albiges L, Rini BI, Peltola K, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study. 

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Sheng X, Ye M, Zou Q, et al. RENOTORCH: toripalimab combined with axitinib versus sunitinib in first-line treatment of advanced renal-cell carcinoma (RCC) - a randomized, open-label, phase III study. 

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Expert oncologists who treat patients with advanced renal cell carcinoma discuss updates from clinical trials presented during the 2023 ESMO Congress.

Combination Regimens Stir Excitement in Advanced RCC

Although the severity of the shortage of chemotherapy agents, particularly with the platinum-based therapies cisplatin and carboplatin, has receded from the heights seen earlier in 2023, clinicians are still dealing with its ramifications and having to strategically manage how they employ certain chemotherapies, according to Alan Tan, MD.

“Currently, I would say that we are OK,” Tan, director of genitourinary medical oncology and an assistant professor in the Department of Internal Medicine at Rush University in Chicago, Illinois, said in an interview with 

. “[However], earlier in the spring, when we got notice that there was a shortage of cisplatin and that we would have to start conserving our usage, we decided as an institution to reserve cisplatin for patients that we deem highly curable. If the intent is not curability and it’s more palliative, we would probably substitute cisplatin with something else such as carboplatin, but weeks [after the announcement of the cisplatin shortage], we got notification that there was a severe shortage in [carboplatin] as well.”

“[Importantly], when we’re talking about curative intent, there are some cancers we treat that we can’t substitute [another agent for platinum therapy],” Tan added. “Testicular cancer, for example, is a highly curable cancer where we were quoting 85% to 90% cure rates for seminoma and nonseminoma. When you have a shortage in such a crucial ingredient that hasn’t changed in several decades, it’s really a big problem. If you can’t cure young men with advanced testicular cancer, that’s a huge issue.”

On June 7, 2023, the National Comprehensive Cancer Network (NCCN) Best Practices Committee shared findings from a survey of 27 NCCN member institutions across the United States gathered from May 23 to 31, 2023. The data showed that 93% of centers were experiencing a shortage of carboplatin and 70% had a shortage of cisplatin. Sixteen percent of centers noted that they had to delay treatment due to needing to reobtain prior authorization for modified treatment plans; centers also reported shortages of methotrexate (67%), 5-FU (26%), fludarabine (11%), paclitaxel (4%), and hydrocortisone (4%).

Although all centers surveyed were still able to treat patients requiring cisplatin without delays or claim denials, only 64% were able to do so for all patients needing carboplatin. Additionally, 20% of centers reported that they were able to continue carboplatin- containing regimens for some current patients, but not all.

In conjunction with the survey results, the NCCN also released a statement in June 2023 on mitigating the impacts of anticancer drug shortages. The statement called upon the federal government, pharmaceutical industry, providers, and payers to contribute to preventing and addressing the impacts of anticancer drug shortages.

The NCCN recommended that the federal government and its agencies place emphasis on fostering a regulatory environment that produces a steady supply of safe, effective anticancer agents. They also noted that the pharmaceutical industry has an obligation to act ethically and morally to ensure the steady supply of anticancer drugs. For providers, the NCCN said use of anticancer agents must be carefully prioritized by efficacy, safety, and cost to achieve pragmatic drug use and maximize societal impact. Finally, they implored payers to put patients first and provide coverage for treatment alternatives to the therapies that are in shortage.

 More recently, on October 5, 2023, the NCCN announced the findings from a follow-up to the June 2023 survey concerning the ongoing chemotherapy shortages, with survey data being collected from September 6 to 27, 2023. Among member institutions surveyed (n = 29), 72% responded that they were still experiencing a carboplatin shortage and 59% were still experiencing a cisplatin shortage.

Although 95% of centers were still able to treat all patients needing a carboplatin-containing regimen according to the intended dosing schedule, the remaining 5% were able to do so with some current patients, but not all. In terms of cisplatin-containing regimens, these rates were 88% and 12%, respectively. Overall, 62% and 71% of centers said they had not received indications from manufacturers or suppliers when carboplatin and cisplatin, respectively, would be readily available. However, all centers indicated that no instances of modified treatment plans due to shortages were denied by payers and no treatment delays occurred because centers reobtained prior authorizations due to shortage- induced treatment plan modifications.

The follow-up also included an expanded survey portion that gauged the rate of shortage regarding other anticancer agents. Outside of cisplatin and carboplatin, centers reported shortages of methotrexate (66%), 5-FU (55%), fludarabine (45%), hydrocortisone (41%), dacarbazine (28%), liposomal doxorubicin (24%), vinblastine (21%), capecitabine (14%), decitabine (14%), docetaxel (10%), paclitaxel (10%), amifostine (7%), and azacitidine (7%).

“Unfortunately, the practices and the patients that suffer the most from the shortage are going to be the ones that don’t have access to referral or academic centers,” Tan commented. “I recently gave a talk at a community practice, and they let me know that they have had to change their practices. Some patients who needed cisplatin could not get it and they had to be referred to higher-volume centers.”

In September 2023, the White House issued a statement acknowledging the issue of the ongoing shortage and attributing it to manufacturing and supply chain issues, giving special mention to cisplatin, carboplatin, and methotrexate, and noting that the shortages were having an adverse effect on the administration’s Cancer Moonshot Initiative. They explained that the FDA has taken steps to address the problem, including working with the manufacturers of generic carboplatin, cisplatin, and methotrexate to increase supplies during the shortages by identifying opportunities to increase manufacturing capacity and lure companies that had stopped making the agents back to the US market—including an instance where 14 lots of cisplatin were imported from an FDA-registered facility outside the United States.

The statement also highlighted a meeting in July 2023 at which the White House Office of Science and Technology Policy gathered leaders involved in the generic oncology drug supply chain, patient advocates, caregivers, and health care providers to get feedback on the effects of the shortages. The White House concluded its statement by affirming that the administration would “continue to work through the FDA, the [US] Department of Health and Human Services, and other agencies to address and prevent drug shortages and mitigate impacts to people facing a cancer diagnosis.”

To combat the ongoing shortage of carboplatin and cisplatin, the most practical approach is using alternative agents and regimens whenever possible, as long as safety and efficacy are not greatly compromised, Tan said. For example, with the April 2023 FDA accelerated approval of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy gained another effective option. Findings from the phase 1/2 EV-103/KEYNOTE-869 (NCT03288545) trial showed that patients who received the combination (n = 121) achieved an objective response rate of 68% (95% CI, 59%-76%), including a 12% complete response rate.

“Of course, this shortage is not limited to cisplatin and carboplatin; there are other shortages in the field, whether it’s BCG or 5-FU shortages,” Tan added. “Earlier in the year, we had a shortage in a different type of treatment for prostate cancer. What differentiates this from the generic drug [shortages] is that this is a brand-name drug that has a high dollar tag, lutetium 

Lu-PSMA-617). There was a problem with quality manufacturing, [as] it was only supplied out of Italy at one point. When they tried to validate sites in the United States, it didn’t meet the optimal standards, so there were delays in getting it to patients. It’s not a curative drug, but it does prolong survival. Patients who were without other options and failed chemotherapies unfortunately died early because they did not have this option.”

Lu vipivotide tetraxetan shortage, which began in March 2023, was classified as resolved by the FDA in October 2023 following efforts to significantly scale up production that led to a doubled weekly production capacity of the agent.

 In contrast, as of November 2023, the FDA drug shortages webpage lists the status of both cisplatin and carboplatin injection as “currently still in shortage.”

“This is one of those issues where we need to come together as a community,” Tan said in conclusion. “The bottom line is there’s not a lot of profits being made in generics. We need to change how we think of incentivizing care in this country.”

NCCN Best Practices Committee carboplatin and cisplatin shortage survey results. National Comprehensive Cancer Network. June 7, 2023. Accessed November 15, 2023. https://www.nccn.org/docs/default-source/oncology-policy-program/NCCN-Drug-Shortage-Survey.pdf 

National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anti-cancer drug shortages. National Comprehensive Cancer Network. Accessed November 15, 2023. https://www.nccn.org/docs/default-source/oncology-policy-program/NCCN-Statement-on-Anti-Cancer-Drug-Shortages.pdf

NCCN Best Practices Committee drug shortage follow-up survey results. National Comprehensive Cancer Network. October 5, 2023. Accessed November 15, 2023. https://www.nccn.org/docs/default-source/oncology-policy-program/NCCN-Drug-Shortages-Survey-Update.pdf

Strengthening the supply chain for cancer drugs. The White House. September 12, 2023. Accessed November 15, 2023. https://www.whitehouse.gov/ostp/news-updates/2023/09/12/strengthening-the-supply-chain-for-cancer-drugs/#:~:text=Unfortunately,%20the%20United%20States%20is,of%20cancer%20treatment%20for%20decades.

FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed November 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic

Novartis confirms unconstrained supply for Pluvicto and continues to significantly expand the number of treatment centers. News release. Novartis. October 26, 2023. Accessed November 15, 2023. https://www.novartis.com/news/media-releases/novartis-confirms-unconstrained-supply-pluvicto-and-continues-significantly-expand-number-treatment-centers

FDA drug shortages. FDA. Revised November 11, 2023. Accessed November 15, 2023. https://www.novartis.com/news/media-releases/novartis-confirms-unconstrained-supply-pluvicto-and-continues-significantly-expand-number-treatment-centers

FDA drug shortages. FDA. Revised November 7, 2023. Accessed November 15, 2023. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Carboplatin%20Injection&st=c 

Although the severity of the shortage of chemotherapy agents, particularly with the platinum-based therapies cisplatin and carboplatin, has receded from the heights seen earlier in 2023, clinicians are still dealing with its ramifications and having to strategically manage how they employ certain chemotherapies. 

Effects of Chemotherapy and Other Anticancer Agent Shortages Linger

It was perhaps inevitable, but nonetheless still striking, when a recently reported commentary discussing a clinically relevant precision cancer medicine topic began by noting a malpractice case lost by an academic medical center due to failure to obtain a specific molecular test that resulted in a serious negative outcome.

In the opinion of this commentator what is most intriguing here is not the fact the clinical situation occurred, that a patient/family sued the provider’s institution, or that the verdict went against the health care organization, but that the authors of this well-written commentary felt it necessary to highlight their argument regarding the need for such testing in this manner.

Have we come to the point where a threat of legal action against providers is the only remaining mechanism left to somehow “open our eyes,” or, stated more directly, force our collective professional, health system, and regulatory communities to deal with the tsunami of clinically relevant data that increasingly characterizes individual patient decision-making?

The article in question discussed DPYD (dihydropyrimidine dehydrogenase) testing for patients scheduled to receive fluoropyrimidine (eg, 5-fluorouracil)-containing chemotherapy, still today a common scenario despite the multidecade use of this class of antineoplastic agents. As the authors highlight in this well-referenced commentary, anywhere from 1% to 2% to as high as possibly 9% of individuals possess germline polymorphisms that predict for the potential that treatment with this class of agents may result in a serious adverse effect (AE).

Similarly, solid nonrandomized evidence suggests that the presence of particular molecular profiles should lead a clinician to initiate the delivery of the fluoropyrimidine antineoplastic drug at a lower dose, thereby avoiding or at least substantially reducing the risk of a high-grade toxic event.

The authors of the commentary advocate for the inclusion of DPYD testing within National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines.

 The presumption appears to be that such inclusion will result in substantial encouragement for routine use of currently available commercial testing.

 And although it is unstated, one might anticipate that failure to obtain the test could increase the potential of a legal judgment against a provider (or institution) if an AE occurred and it was subsequently determined that the individual possessed one of the molecular markers associated with the heightened risk.

There will be no debate from this commentator regarding the data supporting routine testing as a component of standard of care (SOC) or the highly relevant safety benefits for the admittedly relatively limited patient population discovered to have a positive germline finding.

So what are the objections to adding routine DPYD testing to the standard order sets for all patients scheduled to receive a fluoropyrimidine-containing regimen? In addition to the costs of such testing for the rather large number of patients receiving this class of pharmaceutical agents, and the possible delay in initiating systemic therapy to obtain the test results that objectively affect a small proportion of individuals, questions remain regarding the overall effect of testing and a degree of uncertainty persists associated with a decision to automatically employ a lower drug dose in the absence of documented excessive toxicity for that individual.

However, the intent of highlighting this controversy in the current commentary is not to attempt to provide a scholarly or well-reasoned definitive solution, but rather to emphasize just how complex the process of optimizing care delivery has become.

If national group (eg, ASCO, NCCN) guidelines were to label this test as mandated/required SOC or simply declare it to be “strongly recommended,” would this action increase the risk of malpractice claims against health care systems and individual cancer providers?

And this discussion of DPYD testing is truly just the proverbial tip of the iceberg. How long will it be before there are other validated pharmacogenomic tests recommended for noninvestigative use, both specific for antineoplastic agents and the wide variety of noncancer pharmaceuticals taken by patients with cancer? This concern is further heightened by the fact that cancer is a component of aging with risk increasing along with the potential development of other medical conditions for which drug therapy is of clinical value.

This rapidly evolving data tsunami becomes even more evident when we briefly turn our attention to the increasingly rapid developments in precision cancer therapeutics––those strategies whose biological activities and clinical benefit are defined by unique molecular signatures (targets).

Consider, for example, the current list of FDA-approved tumor-agnostic antineoplastic agents where delivery is defined by the demonstrated presence of specific biomarkers rather than the site of origin of the malignancy. In the extensive American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) database (168,423 samples), investigators recently reported that the percentage of molecular abnormalities that would qualify patients for treatment with one of the approved drugs ranged from 1.5% (NTRK fusions) to 15.2% (high tumor mutational burden).

 But even the largest population proportion represents a relatively small minority of all patients (1 of 6 individuals) and the lowest percentage is less than 1 in 50 of those tested.

Should all patients with advanced cancers who have “failed to respond to or progressed on SOC therapy” undergo an evaluation for the potential presence of all molecular abnormalities associated with an FDA-approved antineoplastic agent, even if the likelihood of finding the relevant biomarker is less than 1% to 2%?

Furthermore, it is highly likely that the rapid development of antibody– drug conjugates will substantially accelerate efforts to specifically target unique molecular abnormalities that may characterize small population groups across multiple tumor types (eg, the anti-HER2 agent fam-trastuzumab deruxtecan [Enhertu]).

There is no intent in writing this commentary to suggest that the major justification for ensuring essential clinical decision support for the massive quantity of molecular data that will soon (if it has not already) overwhelm even the most dedicated physician is the risk of a legal claim of malpractice.

Rather, the goal in highlighting this development is to attempt to raise awareness of the critical issue of information overload and the need for multiple involved parties to actively and aggressively search for appropriate, effective, and fiscally rational solutions. 

Baker SD, Bates SE, Brooks GA, et al. DPYD testing: time to put patient safety first. 

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Hertz DL. Assessment of the clinical utility of pretreatment DPYD testing for patients receiving fluoropyrimidine chemotherapy. 

. 2022;40(33):3882-3892. doi:10.1200/JCO.22.00037

Hockings JK, Pasternak AL, Erwin AL, Mason NT, Eng C, Hicks JK. Pharmacogenomics: an evolving clinical tool for precision medicine. 

. 2020;87(2):91-99. doi:10.3949/ccjm.87a.19073

Gouda MA, Nelson BE, Buschhorn L, Wahida A, Subbiah V. Tumor-agnostic precision medicine from the AACR GENIE database: clinical implications. 

. 2023;29(15):2753-2760. doi:10.1158/1078-0432.CCR-23-0090

Tarantino P, Pestana RC, Corti C, et al. Antibody-drug conjugates: smart chemotherapy delivery across tumor histologies. 

. 2022;72(2):165-182. doi:10.3322/caac.21705

LI BT, Meric-Bernstam F, Bardia A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with solid tumors harboring specific HER2-activating mutations (HER2m): primary results from the international phase II DESTINY-PanTumor01 (DPT-01) study. 

. 2023;34(suppl 2):S459-S460. doi:10.1016/j.annonc.2023.09.1840

From the Editor

The goal in highlighting this development is to attempt to raise
awareness of the critical issue of information overload and the need for
multiple involved parties to actively and aggressively search for appropriate,
effective, and fiscally rational solutions.

Vol. 24/No. 20 | Oncology Live®

First-in-Class YAP/TEAD Inhibitor Demonstrates Early Efficacy Targeting Hippo Pathway

Combination Regimens Stir Excitement in Advanced RCC

Effects of Chemotherapy and Other Anticancer Agent Shortages Linger

When Will We Acknowledge Information Overload in Oncology?