Emerging Combination Therapies in Renal-Cell Carcinoma: Applying the Lessons from Clinical Trials to Clinical Practice

March 2021 Clinical Trials to Clinical Practice

With commentaries by
Kara M. Olivier, NP
Nurse Practitioner
Massachusetts General Hospital Cancer Center
Boston, MA

Kidney cancer is the third most common type of genitourinary malignancy worldwide.1 In the United States, approximately 74,000 people are diagnosed with kidney cancer each year, with nearly 15,000 dying of the disease.2 Men are affected at about twice the rate as women, with lifetime risks of 2% and 1%, respectively.2 The overall incidence of kidney cancer has been on the rise since the 1990s, likely due to an increasing number of incidental radiographic diagnoses, which detect malignancies at an earlier stage.1 Most patients are diagnosed between 65 and 74 years of age.2

The most common form of kidney cancer is renal-cell carcinoma (RCC), which accounts for about 90% of all cases.2 RCC can be subtyped by either clear-cell or non–clear-cell histology; since 80% to 90% of patients with RCC have clear-cell disease, most clinical trials have focused and continue to focus on this patient population.3

In the mid-2000s, recommendations for treating RCC began trending away from immunotherapies, such as interferon-alpha, and toward tyrosine kinase inhibitors (TKIs), such as sunitinib.3 The use of immunotherapies is now returning to the spotlight, as combination regimens involving monoclonal antibodies have demonstrated prolonged survival among certain newly diagnosed patients.3,4

Once more, the first-line treatment paradigm for patients with RCC is shifting, necessitating familiarity with the latest findings. This article reviews pivotal clinical trials of recent and emerging combination therapies for patients with RCC. Additional discussions and commentary offer practical strategies to manage common adverse events, promote long-term treatment adherence, and overcome barriers to therapy, all of which aim to bridge the gap between clinical trials and clinical practice.

Commentary by Kara Olivier, NP: I’ve been working in genitourinary oncology for 16 years. When I first started, patients had limited treatment options, such as interferon and high-dose IL-2 [interleukin-2] did not consistently provide the outcomes we wanted for patients and often had unacceptable toxicity. Then targeted agents like sorafenib and sunitinib were introduced, followed by everolimus and temsirolimus, all of which really changed prognosis and opened up a range of new treatment strategies. In subsequent years, various immunotherapy combinations involving nivolumab, ipilimumab, pembrolizumab, and cabozantinib demonstrated improved overall survival, with the latter agent also meeting this end point as a monotherapy. While combination therapy with avelumab slowed disease progression, survival data were immature upon publication. For a lot of different cancers, not just renal-cell carcinoma, immunotherapy has widened the field. We are now in an era where we are looking at ways to optimize combination therapies to improve patient outcomes and survival further.

Efficacy of Recently Approved and Emerging Combination Therapies

Since 2018, the US Food and Drug Administration has approved 4 first-line combination regimens for the treatment of RCC: nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, and nivolumab plus cabozantinib.5-8 These regimens were approved based on results from 3 phase 3 trials: CheckMate-214, KEYNOTE-426, JAVELIN Renal 101, and CheckMate-9ER.5-8 Recent findings from these trials are reviewed below.

CheckMate-214: Nivolumab plus Ipilimumab

The CheckMate-214 trial compared standard-of-care sunitinib (a vascular endothelial growth factor receptor [VEGFR] TKI) with a combination of nivolumab (a programmed death-1 [PD-1] immune checkpoint inhibitor antibody) plus ipilimumab (an anti–cytotoxic T-lymphocyte antigen 4 [CTLA-4] antibody).4 The trial enrolled a total of 1096 individuals with treatment-naïve, advanced, clear-cell RCC, 847 of whom were stratified as intermediate- or poor-risk patients.4

At 42 months, among intermediate- and poor-risk participants, 52% of those who received nivolumab plus ipilimumab were still alive, compared with 39% of patients in the sunitinib group (Table 1).9 In the same population, the objective response rate (ORR) with nivolumab plus ipilimumab was 42%, versus 26% with sunitinib.9 Complete response (CR) rates of 10% and 1%, respectively, were reported in the 2 groups.9 CRs to nivolumab plus ipilimumab were durable, with 84% of patients maintaining their response at 42 months.9

The above data represent the longest follow-up of any immunotherapy combination among patients with treatment-naïve RCC.9 Nivolumab plus ipilimumab is currently approved as first-line therapy for intermediate- and poor-risk patients with RCC, as well as those who have received prior anti-angiogenic therapy.9

It is worth noting that patients with favorable-risk disease fared worse with nivolumab plus ipilimumab than those who received sunitinib, both in terms of ORR and progression-free survival (PFS).4 Overall survival (OS) differences were not statistically significant.4

KEYNOTE-426: Pembrolizumab plus Axitinib

As with the CheckMate-214 trial, KEYNOTE-426 was designed to compare the combination of a VEGFR-TKI (axitinib) and a PD-1 inhibitor (pembrolizumab) with sunitinib monotherapy.10 The trial enrolled a total of 861 patients with treatment-naïve clear-cell RCC, 592 of whom were classified as being in an intermediate- or poor-risk category.10

With a median follow-up of 27 months, most recent results show that pembrolizumab plus axitinib was associated with a significantly longer 2-year OS rate of 74%, compared with 66% with sunitinib alone (P <.0001; Table 2).11 Similarly, the immunotherapy combination regimen versus sunitinib led to significantly better ORR (60% vs 40%, respectively; P <.0001), CR rate (9% vs 3%, respectively), and median duration of response (23.5 vs 15.9 months, respectively).11 These benefits were observed across all subgroups, including those stratified by risk and programmed death-ligand 1 (PD-L1) expression.11

Pembrolizumab plus axitinib is approved as first-line therapy for patients with advanced RCC, regardless of PD-L1 expression status.7

JAVELIN Renal 101: Avelumab plus Axitinib

The JAVELIN Renal 101 trial also compared sunitinib with axitinib, this time in combination with avelumab—a checkpoint inhibitor that targets PD-L1, thereby acting through a slightly different mechanism than pembrolizumab, which targets the PD-1 receptor.12 The trial enrolled a total of 886 patients with advanced clear-cell RCC, among whom 690 were in the intermediate- or poor-risk group.12

Recently published updated efficacy results, with a median follow-up of approximately 19 months, showed the superior efficacy of avelumab plus axitinib compared with sunitinib (Table 3).13 The immunotherapy combination was associated with a median PFS of 13.3 months, compared with 8.0 months for sunitinib (P <.0001); a slightly greater benefit was observed among patients who were PD-L1–positive (13.8 vs 7.0 months, respectively; P <.0001).13 Across all patients, the ORR with avelumab plus axitinib was 52.5% (95% confidence interval [CI], 47.7-57.2), compared with 27.3% with sunitinib (95% CI, 23.2-31.6), which included respective CR rates of 3.8% and 2.0%.13 OS data were still immature at the time of the analysis.13

Avelumab plus axitinib is approved as first-line therapy for patients with advanced RCC, regardless of PD-L1 expression status.5


The most recently approved immunotherapy combination for patients with RCC is nivolumab plus the TKI cabozantinib, which inhibits VEGFR, MET, AXL, and multiple other targets.8,14,15 Approval was based on the CheckMate-9ER trial, which compared this combination with sunitinib in patients with treatment-naïve, advanced RCC.16 The study met major primary and secondary end points, including superior PFS, OS, and ORR, all while demonstrating a favorable safety profile (Table 4).16 Out of 651 patients, 22.6% had favorable risk, 57.6% had intermediate risk, 19.7% had poor risk, and 24.9% had PD-L1 expression of at least 1%.17 After a median follow-up of 18.1 months, the combination immunotherapy regimen demonstrated superior median PFS over sunitinib (16.6 vs 8.3 months, respectively; P <.0001) and OS (hazard ratio, 0.60; medians not reached) across subgroups for risk and PD-L1 expression status.17 In the combination group, 55.7% of patients achieved an objective response, compared with 27.1% of patients in the sunitinib group (P <.0001), with respective CR rates of 8.0% and 4.6%.17

Planned and Ongoing Trials

At least 5 additional phase 3 clinical trials either plan on evaluating or are currently evaluating various other immunotherapy combinations for patients with advanced RCC.18-22 Since results are not yet available for any of these studies, trial names and combinations have been listed in Table 5, for future reference.

Commentary by Kara Olivier, NP: For many patients, understanding the clinical trial data is important and provides them an opportunity to be an active participant in their care. The challenge with immunotherapy is that responses can vary significantly from patient to patient. Patients may have no response and no toxicity, while others have unacceptable toxicity but a great response clinically and radiographically. Still, we try to predict and plan as much as possible to ensure the best outcome. When we consider treatment options, we really think about a patient’s past medical history, current performance status, while prioritizing their goals of treatment.

Safety of Recently Approved and Emerging Immunotherapy Combinations

Among first-line-approved immunotherapy combinations with rates available for each common adverse event (AE), avelumab plus axitinib and pembrolizumab plus axitinib have similar safety profiles, whereas nivolumab plus ipilimumab therapy is associated with a slightly different set of common AEs (Table 6).4,11,12

In phase 3 trials, the 3 most common AEs of any grade associated with nivolumab plus ipilimumab therapy were fatigue, pruritus, and diarrhea.4 In contrast, patients taking one of the 2 combination therapies that included axitinib were more likely to experience hypertension and less likely to experience pruritus.11,12 The most common grade ≥3 AE among patients receiving nivolumab plus ipilimumab was an increased lipase level,4 compared with hypertension among those being treated with either avelumab plus axitinib or pembrolizumab plus axitinib.11,12

Although a quick comparison of frequencies of AEs across phase 3 trials may suggest that nivolumab plus ipilimumab is the best-tolerated regimen, it is notable that the rates of AEs reported in the nivolumab-plus-ipilimumab trial included only treatment-related AEs, not those “of any cause,” as reported with the trials involving axitinib combination therapies. Similarly, relative tolerability is difficult to discern based on rates of treatment discontinuation, as no dose reductions were allowed in the nivolumab-plus-ipilimumab trial, which had a treatment-related discontinuation rate of 22%.4 This contrasts with discontinuation rates between 8% and 11% in the axitinib trials, noting that 20% to 42% of patients had dose reductions.4,10,12 Dose delays were more common in the phase 3 pembrolizumab-plus-axitinib trial, at 70%, compared with respective rates of 27% and 58% for ipilimumab and nivolumab.4,11 Delays were not reported with the avelumab-plus-axitinib regimen.

For nivolumab plus cabozantinib, specific rates for the most common AEs are unavailable; however, the safety of this combination is consistent with AE profiles for each agent alone.8,16,17 In the CheckMate-9ER trial, at least 20% of patients reported diarrhea, nausea, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, stomatitis, rash, hypertension, hepatotoxicity, hypothyroidism, dysgeusia, musculoskeletal pain, decreased appetite, cough, and/or upper respiratory tract infection. Comparing cohorts, 60.6% of patients treated with the nivolumab-plus-cabozantinib regimen experienced grade 3 treatment-related AEs, compared with 50.9% in the sunitinib group.17 Treatment-related discontinuation of both nivolumab and cabozantinib was reported in 3.1% of patients, whereas discontinuation of either agent occurred in 15.3% of patients, with discontinuation of cabozantinib more common than discontinuation of nivolumab (6.6% vs 5.6%, respectively). Of note, nivolumab plus cabozantinib offered significantly better quality of life than sunitinib, possibly making it a favored regimen over previously approved immunotherapy combinations; however, head-to-head trials among the various combinations have not been (and are unlikely to be) conducted.23

Commentary by Kara Olivier, NP: Compared with nivolumab/ipilimumab, toxicities from nivolumab/cabozantinib or pembrolizumab/axitinib are somewhat more straightforward to manage. If a patient is experiencing a toxicity on combination TKI/IO therapy it can be helpful to temporarily hold the TKI to better understand if the toxicity is from TKI therapy or IO therapy.

We have patients receiving cabozantinib/nivolumab through the CheckMate-9ER trial with some completing therapy with little to no interruption. If patients do require treatment interruption for medical care, such as dental care, we can schedule treatment breaks that allow for adequate healing and recovery.

Managing Immune-Related Adverse Events

Immunotherapies may cause immune-related AEs, with distinct safety profiles associated with PD-1/PD-L1 inhibitors (ie, checkpoint blockers) versus CTLA-4 inhibitors.24 CTLA-4 inhibitors (eg, ipilimumab) trigger immune-related AEs more often than do checkpoint blockers (eg, nivolumab, avelumab, and pembrolizumab); when combined, as with nivolumab plus ipilimumab, immune-related AEs become even more common. In the CheckMate-214 trial, for example, 79.7% of patients who received nivolumab plus ipilimumab experienced immune-related AEs of any grade, compared with 38.2% of patients in the JAVELIN Renal 101 trial, who were treated with avelumab plus axitinib.4,12

Because immunotherapy can affect almost any organ system, a wide variety of immune-related AEs can occur.24 Management depends on the specific combination regimen used, the organ system or systems affected, and the severity of the AE/AEs.23

Generally, with grade 1 immune-related AEs, immunotherapies are continued alongside more frequent monitoring, with the exception of pneumonitis, which necessitates a dose-hold until resolution on repeat imaging.23 With grade 2 immune-related AEs that are predominantly inflammatory in nature, such as colitis or hepatitis, a dose-hold is recommended, as well as the commencement of prednisone therapy.23 Grade ≥3 immune-related AEs generally require more intensive interventions, such as permanent discontinuation of the agent, hospitalization, and/or administration of more potent immunosuppressives, such as infliximab.23

Among patients being treated with an immunotherapy/TKI combination, the TKI is typically held first, in order to determine if symptoms improve, prior to holding the checkpoint blocker.25 For patients with immune-related AEs that affect the endocrine system who do not experience severe symptoms, it may be possible to continue combination immunotherapy if appropriate hormone supplementation is also provided.23

Commentary by Kara Olivier, NP: Common toxicities we encounter with immunotherapy include colitis, skin toxicity, pneumonitis, hypophysitis, and other endocrinopathies, although almost any part of the body can be affected. The key is early intervention.

In the past, with earlier agents, we used to say, “Make sure you have antidiarrheal medications, oral care support, and skin care options at home.” Now with immunotherapy we know it’s important for patients and providers to communicate as soon as symptoms occur so we can strategize early and apply the best interventions.

In my conversations with colleagues, everyone has a slightly different approach to best interventions and timing. At MGH we brought together a group of colleagues from various specialties (endocrinology, dermatology, neurology, pulmonology, gastroenterology, nephrology, cardiology) called the Serious Immunotherapy Complications Service that specifically cares for patients with IO toxicity. Knowing who your experts are and how to ensure early communication can decrease length of illness and improve symptoms early.

Setting Expectations to Achieve Long-Term Adherence

Previous research has shown that patient adherence to cancer therapy declines over time.26 Effective management of AEs may reduce symptoms and thus improve treatment adherence; however, this is a reactive approach, rather than a proactive strategy. Proactively, healthcare providers should be aware that certain patients are less likely to adhere to therapy than others— namely, those with negative mood, greater symptom burden, later-stage disease, financial hardship, and more complex medication regimens.25 Identification of the above factors may allow for proactive interventions to improve adherence—for example, with psychosocial support for patients who are experiencing depression and/or anxiety.

In addition to the above factors, patient expectations prior to starting therapy are predictive of long-term adherence.27 Those with negative expectations more often report low tolerability of treatment, particularly in the presence of AEs within the first 3 months.27 When negative expectations are encountered, experts recommend several psychoeducational techniques, such as framing information in a positive light and optimizing coping strategies.27 For example, by teaching patients that AEs are a sign that their medication is working, they will be better equipped to cope with their symptoms and therefore continue to take their medications as prescribed.27 This is critical, they should be reminded, as greater adherence is associated with greater survival.27

Commentary by Kara Olivier, NP: Adherence to medications is an important part of patient and family education when starting treatment. There are many reasons patients stop and start medications outside of the recommended schedule, and understanding those barriers can improve adherence and tolerability.

As an example: It is really important to discuss drug half-life with patients. Shorter half-life with axitinib requires twice-per-day dosing versus cabozantinib which has a longer half-life. The half-life of these medications impacts days to recovery from toxicity and effectiveness of therapy.

Beyond discussing the half-life of medications with patients, it’s helpful to discuss key points and goals of treatment. Patients and families are motivated, and ensuring they feel a part of the decision-making is helpful for a strong foundation.

When patients are on a clinical trial, they go home with a pillbox and they go home with a calendar. They have to write down every day that they took their pills. Then we go over that calendar. If they’ve missed a dose here and there, I sit down with them and say, “It looks like you missed a dose. Tell me a little bit about what happened that day.” Then I say, “If that happened more than one day, please feel free to reach out to us so we can strategize together.” I think the repetitiveness of reminding patients for the rationale of recommended treatment can help them feel empowered and that they are a part of the plan.

Recognizing and Overcoming Barriers to Access

Whereas some patients may struggle with treatments received, others may struggle to access treatment in the first place, particularly as health insurance premiums and the cost of therapies continue to rise.28 Multiple barriers to access may prevent patients with RCC from receiving the care they need. It is imperative for healthcare providers to be aware of these obstacles and ways in which to overcome them.

Health System Structure

The structure of the healthcare system itself is the first barrier to timely, high-quality care. Patients with cancer may be receiving care from multiple providers at multiple facilities, which can lead to issues with coordination, communication, transport, and payment.28

Health Insurance

Type of health insurance can have a dramatic impact on the level of care that patients with cancer receive and their ultimate treatment outcomes.28 For example, one study that involved more than 740,000 patients with cancer in California found that those with prostate cancer who had public health insurance were more than 3 times as likely to be diagnosed with stage IV disease as were those with a private payer (18.6% vs 5.6%, respectively).29 Further, 5-year survival rates were almost twice as high among those who were privately insured (69.5% vs 36.7%).29 Timely diagnosis was not the only issue, either. The same study found that patients with stage III colon cancer were significantly more likely to receive standard adjuvant chemotherapy during first-line treatment if they had insurance from the Department of Defense versus public insurance (83% vs 51%, respectively).29

These issues may be compounded by narrow insurance networks, in which it is difficult for patients with public health insurance to find providers, particularly specialists.28 Even when providers are located, they may have delayed appointment times and may be unable to offer patients the latest, most effective treatments.28

For all patients, even those with private insurance, navigating healthcare plans can be challenging; issues with enrollment and authorization can be significant barriers to accessing care.28


A cancer diagnosis can incur both medical and nonmedical costs that may prevent patients from affording appropriate care.28 Medical fees often lack transparency, so it is difficult for patients to plan for oncoming financial burdens, or to compare costs with respect to providers, payers, or types of therapy.28 Nonmedical costs vary widely, from the cost of transportation to the cost of lost wages from missing work.28

Individual Factors

A broad array of individual factors may act as barriers to healthcare access, including patient location, culture, language, and health literacy. Patients with cancer who live in rural areas, for example, may be far from major treatment centers and therefore have limited access to the latest therapies and clinical trials.28 Some cultures may have fatalistic beliefs about a cancer diagnosis, such that treatment is not pursued and death is simply accepted.28 In other cultures, health issues may not be openly discussed or individuals may not want to sacrifice familial responsibilities in order to seek treatment.28 Language barriers can also impede high-quality care, as patients are less likely to follow recommendations if they are unable to understand the communication they receive from their healthcare provider. Even when patients speak English as their first language, low health literacy can be an obstacle to complete understanding of their situation.28

Overcoming Barriers to Access with Nurse Navigators

This wide variety of barriers to access may require an equally wide set of solutions. Many solutions can be achieved with the help of a nurse navigator, via both medical and nonmedical support.28 Nurse navigators can serve as a connector between patients and their needs, to overcome the barriers to care described above.28 For example, nurse navigators may:

  • Arrange affordable and timely transportation for a patient (health system structure)
  • Ensure that patients are following up with insurance companies (health insurance)
  • Educate patients about medication copay cards and other financial support systems (costs)
  • Interpret complex medical language and treatment options for patients with lower health literacy (individual factors).

Commentary by Kara Olivier, NP: Each healthcare organization has an individualized approach to creating access to care for patients receiving cancer care.

When we meet patients for the first time, our responsibility as healthcare providers is to understand their diagnosis, create and communicate a plan while considering their beliefs, fears, barriers, and perceptions of their care. Are there language barriers? Are there literacy barriers? What is life like at home for the patient and family? Are they caring for young children or elderly parents? Do they have a job that is necessary, important, or meaningful to them?

Understanding where patients are coming from can guide the best educational strategy and how we should approach their care in a way that meets their needs and wishes. It’s where listening is one of the most important skills we can bring to visits.

It is also important to remember that some patients have never faced a serious illness so the intricacies of multiple appointments, specialty pharmacies, serial lab work, and imaging can be overwhelming. Managing high copays for specialty medications is another factor that can be overwhelming for patients and families. Providing information regarding copay relief and available copay supports can allay fears regarding possible financial toxicity. Our goal is to reassure our patients that we have resources at hand and that we will work endlessly to help them access the treatment they need.


Over the past 3 years, immunotherapy combinations have come to the forefront of care for patients with RCC. Although both avelumab plus axitinib and pembrolizumab plus axitinib are approved for first-line therapy in all patients with RCC, nivolumab plus ipilimumab is approved for first-line treatment of patients with intermediate- and poor-risk disease. Still, other combinations are on the horizon, with nivolumab plus cabozantinib the most likely candidate for approval in the near future.

Healthcare providers need to remain aware of differences in both efficacy and safety between these treatment options by staying up to date with relevant clinical trials. Furthermore, knowledge of clinical techniques, including AE management strategies, can ensure that these medications are delivered safely. To guarantee that medications are received in a timely, appropriate fashion, healthcare providers need to set patient expectations early and work with nurse navigators to overcome barriers to access.


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  9. Opdivo (nivolumab) plus Yervoy (ipilimumab) demonstrates continued survival benefit at 42-month follow-up in patients with previously untreated advanced or metastatic renal-cell carcinoma [press release]. February 15, 2020. Princeton, New Jersey and Amaleda, California.
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  12. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103-1115.
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  14. Exelixis announces submission of supplemental new drug application to U.S. Food and Drug Administration for Cabometyx® (cabozantinib) in combination with Opdivo® (nivolumab) for advanced renal-cell carcinoma [press release]. August 24, 2020. Amaleda, California.
  15. CABOMETYX (cabozantinib) [package insert]. Alameda, CA; Exelixis, Inc.; 2019.
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  18. Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal-Cell Carcinoma (CLEAR). https://clinicaltrials.gov. Updated September 2, 2020. Accessed September 2, 2020.
  19. Pembrolizumab (MK-3475) Plus Epacadostat vs Standard of Care in mRCC (KEYNOTE-679/ECHO-302). https://clinicaltrials.gov. Updated October 30, 2019. Accessed September 2, 2020.
  20. A Study of Atezolizumab in Combination With Cabozantinib Compared to Cabozantinib Alone in Participants With Advanced Renal-Cell Carcinoma After Immune Checkpoint Inhibitor Treatment (CONTACT-03). https://clinicaltrials.gov. Updated September 2, 2020. Accessed September 2, 2020.
  21. A Study of Bempegaldesleukin (NKTR-214: BEMPEG) in Combination With Nivolumab Compared With the Investigator’s Choice of a Tyrosine Kinase Inhibitor (TKI) Therapy (Either Sunitinib or Cabozantinib Monotherapy) for Advanced Metastatic Renal-Cell Carcinoma (RCC). https://clinicaltrials.gov. Updated September 2, 2020. Accessed September 2, 2020.
  22. Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal-Cell Carcinoma (COSMIC-313). https://clinicaltrials.gov. Updated August 28, 2020. Accessed September 2, 2020.
  23. New first-line treatment option for metastatic kidney cancer, according to results of phase 3 study [press release]. www.esmo.org. Updated September 19, 2020. Accessed September 21, 2020.
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Last modified: August 10, 2023

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