Frontline pembrolizumab (Keytruda) induced clinically meaningful improvements in the health-related quality of life (HRQoL) of patients with microsatellite instability-high (MSI-H) and/or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) compared with standard-of-care (SOC) chemotherapy, according to new research presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

“These findings further support use of pembrolizumab as a standard of care for first-line treatment of patients with MSI-H/dMMR mCRC,” Thierry André, MD, the study’s lead author, said in an oral presentation at the virtual conference.

The Phase III KEYNOTE-177 study analyzed 294 treatment-naïve U.S. patients with MSI-H and/or dMMR mCRC. In that study, researchers demonstrated that, in comparison to chemotherapy (mFOLFOX6 or FOLFIRI) with or without bevacizumab or cetuximab, pembrolizumab alone provided superior progression-free survival (PFS). In the current analysis, the investigators found that immunotherapy sparked an increase in HRQoL over 2 years compared with chemotherapy.

Patients were randomized 1:1 to take either pembrolizumab (n=152) or SOC chemotherapy (n=142) with or without bevacizumab or cetuximab. In a follow-up at 18 weeks, clinically meaningful improvement was found based on the results of 2 validated, self-reported questionnaires, measuring against a baseline score of 0. The QLQ-C30 global health status quality-of-life scale found a least-squares mean (LSM) score change of 8.96 (95% CI, 4.24-13.69; P = .0002) and the EQ-5D VAS demonstrated an LSM increase of 7.38 (95% CI, 2.82-11.93; P = .0016) for patients receiving pembrolizumab compared with chemotherapy. According to data presented at the ESMO virtual congress, during the time period 18-45 weeks after the start of treatment, the LSM score for patients receiving pembrolizumab improved by another 5-10 points, while the score for those taking chemotherapy dropped by several points.

Another questionnaire, QLQ-CR29, showed that patients taking pembrolizumab reported improvements in anxiety, weight and, for men, sexual interest between baseline and week 18; patients taking chemotherapy also saw an improvement in anxiety but reported declines in body image and, among men, sexual interest. Sexual interest dropped for women on both regimens.

Moreover, time to deterioration, including physical and social functioning and fatigue, was delayed in patients who received pembrolizumab versus chemotherapy (HR, 0.50; 95% CI, 0.32-0.81; P=0.0016). For instance, in looking at the probability of no physical deterioration during

that period, researchers noted 29 documented events in patients taking pembrolizumab compared with 45 events for patients taking chemotherapy.

Adverse effects such as urinary frequency, abdominal pain, bloating and stoma care problems improved over time with pembrolizumab, while issues including buttock pain, dry mouth, alopecia, taste alterations and sore skin increased with chemotherapy.

These data provide further proof that pembrolizumab monotherapy is a viable treatment for patients with MSI-H and/or dMMR mCRC in the first-line setting, said Andre, head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, emphasized that meaningful improvements in quality of life were seen with pembrolizumab but not with chemotherapy, adding that further study is warranted. André did caution that results were limited to the treatment period, and while this immunotherapy works well, especially in the PD-L1 pathway, its usefulness can be limited depending on whether a patient’s disease is resistant to treatment.

Andre T, Amonkar M, Norquist J, et al. Health-related quality of life (HRQoL) in patients (pts) treated with pembrolizumab (pembro) vs chemotherapy as first-line treatment in microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC): Phase III KEYNOTE-177 study. Presented at: European Society of Medical Oncology Virtual Congress 2020; September 19- 21, 2020; Virtual. Abstract 396O.

Articles

Frontline pembrolizumab induced clinically meaningful improvements in the health-related quality of life of patients with microsatellite instability-high and/or mismatch repair-deficient metastatic colorectal cancer.

Frontline Pembrolizumab Improves Health-Related QOL in DNA Repair-Deficient Metastatic CRC

Treatment with durvalumab (Imfinzi), both as a monotherapy and in combination with tremelimumab, failed to improved overall survival (OS), compared with chemotherapy, in patients with metastatic urothelial cancer (UC), according to phase 3 findings presented at the 2020 European Society for Medical Oncology virtual congress.1

However, secondary analyses suggested that tremelimumab bolstered the anti-tumor activity of durvalumab, particularly in patients whose tumors had high PD-L1 expression.

In introducing the study, investigator Thomas Powles, MBBS, MRCP, MD, explained that although platinum-based chemotherapy yields initial high responses as first-line treatment for metastatic urothelial cancer, “patients relapse, and long-term, durable remissions are rare.

“Both atezolizumab [Tecentriq] and pembrolizumab [Keytruda] are approved in the cisplatin-ineligible, PD-L1-positive population in this frontline space. Their approval is based off 2 single-arm trials with relatively modest numbers.2,3 We don't currently have any mature, randomized overall survival data in this setting,” added Powles, professor of genitourinary oncology, director of Barts Cancer Centre, Queen Mary University of London, United Kingdom.

Durvalumab is approved by the FDA for the treatment of platinum-refractory, metastatic UC. Previous research has indicated that tremelimumab alone and the combination of durvalumab plus tremelimumab shows activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.4,5

The DANUBE trial evaluated durvalumab, with or without tremelimumab, vs platinum-based chemotherapy, as first-line treatment for metastatic UC (NCT02516241). The study included 1032 patients with untreated, unresectable, locally advanced, or metastatic UC.

Patients were randomized 1:1:1 to receive 1500 mg durvalumab IV once monthly until progression (n = 346); 1500 mg durvalumab IV once monthly until progression plus 75 mg tremelimumab once monthly for up to 4 doses (n = 342); and a standard-of-care chemotherapy regimen of gemcitabine plus cisplatin or carboplatin up to 6 cycles (n = 344). Randomization was stratified by cisplatin eligibility, PD-L1 status (high or low), and presence or absence of liver and/or lung metastases.

Baseline characteristics such as age, region, and pure transitional cell carcinoma were generally well balanced among the treatment groups.

Co-primary end points consisted of overall survival (OS) for durvaluamb vs chemotherapy in patients with high PD-L1 expression and OS for durvalumab plus tremelimumab vs chemotherapy in the intention-to-treat (ITT) population.

The minimum follow-up time was 34 months, and median follow-up for survival was 41.2 months for all patients.

Median OS for patients in the durvalumab-only group was 14.4 months vs 12.1 months for the chemotherapy group (HR, 0.89; 95% CI, 0.71-1.11) In the durvalumab plus tremelimumab cohort. Median OS was 15.1 months vs 12.1 months for the chemotherapy group (HR, 0.85; 95% CI, 0.72-1.02).

In regards to anti-tumor activity, median duration of response in the ITT population for patients in the durvalumab-only, durvalumab plus tremelimumab, and chemotherapy groups was 9.3 months (95% CI, 5.8-20.5), 11.1 months (95% CI, 7.9-18.5), and 5.7 months (95% CI, 5.6-6.2), respectively.

Median duration of response in the PD-L1-high population in the durvalumab only, durvalumab plus tremelimumab, and chemotherapy groups was 18.5 months (95% CI, 7.6-not estimable), 10.0 months (95% CI, 7.4-18.7), and 5.8 months (95% CI, 5.1-7.0), respectively.

Treatment-related adverse events occurred in 56% of the durvalumab cohort, 75% of the durvalumab plus tremelimumab cohort, and 90% of the chemotherapy cohort. Both durvalumab monotherapy and durvalumab/tremelimumab had manageable safety profiles, and no new safety signals were observed.

Reflecting on the results, Powles commented, “Overall, with a median survival 41 months, this DANUBE data has the most robust data set to date. I think it gives a good impression of the role of both monotherapy and the combination in this environment.”

He added, “While the trial was negative, it does give us some provocative data… for future trials.

1. Powles TB, van der Heijden MS, Gauna Castellano D, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Paper presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 697O.

2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 

2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2

3. Balar AV, Galsky MD, Rosenberg JE, IMvigor 210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. 

2017; 389(10064)67-76. doi: 10.1016/S0140-6736(16)32455-2

4. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. 

2020;26-61-70. doi:10.1158/1078-0432.CCR-19-1635

5. Balar AV, Mahipal A, Grande E, et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Paper presented at: 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL.

Durvalumab, with or without tremelimumab, failed to meet its primary end point of overall survival in patients with metastatic urothelial cancer.

Durvalumab Monotherapy, Combination Fail to Improved OS in Metastatic Urothelial Carcinoma

The benefits conferred by the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the first-line treatment of advanced renal cell carcinoma (RCC) remained durable after 4-year follow-up compared with treatment with sunitinib (Sutent).

Investigators also reported that a subgroup of patients with 1 or more target kidney lesions experienced kidney tumor reduction and other benefits from the combination treatment.
The research was presented at the 2020 European Society for Medical Oncology virtual congress.1

“Nivolumab plus ipilimumab was the first immunotherapy combination to demonstrate an overall survival advantage over sunitinib in intermediate- and poor-risk patients with advanced renal cell carcinoma,” CheckMate -214 investigator Laurence Albiges, MD, PhD, said in a press release.2 “Now, after 4 years, the durable efficacy seen in CheckMate -214 represents important progress towards the aim of changing survival expectations for these patients,” added Albiges, Head of Genitourinary Unit, Gustave Roussy Institute, Villejuif, France.

The randomized, open-label phase 3 CheckMate -214 trial evaluated the combination of nivolumab and ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC.

Patients in the combination group (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg nivolumab every 2 weeks. Patients in the sunitinib group (n = 546) received 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Treatment was given until progression or unacceptable toxic effects.

Primary end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in an intermediate- to poor-risk patient population. In addition, non-prespecified, post hoc exploratory efficacy analyses were performed in a subgroup of study patients who had not undergone prior nephrectomy and who had 1 or more target kidney lesions.

In intermediate- to poor-risk patients treated with nivolumab/ipilimumab, median OS was 48.1 months, compared with 26.6 months in patients who received sunitinib (HR, 0.65; 95% CI, 0.54-0.78). The 4-year OS rate for the combination treatment and sunitinib groups was 50.0% and 35.8%, respectively. ORR was also higher in patients receiving combination treatment versus sunitinib, with more ongoing responses in intermediate- to poor-risk patients (65% vs 50%, respectively). Median duration of response was not reached in the combination treatment arm and was 19.7 months for sunitinib.

Analysis of patients in the intention-to-treat (ITT) population with 48 months’ follow-up also pointed to the benefits of nivolumab/ipilimumab treatment. Median OS was not reached for all patients in the combination treatment group vs 38.4 months in the sunitinib group (HR, 0.69; 95% CI, 0.59-0.81), with 4-year OS rates of 53.4% and 43.3%, respectively. ORR was higher in patients receiving nivolumab/ipilimumab, with more ongoing responses compared to patients receiving sunitinib (65% vs 52%). Median duration of response was not reached in patients treated with nivolumab/ipilimumab and was 23.7 months in the sunitinib group.

In the subgroup of patients with 1 or more target kidney lesions, ORR was 34% in the nivolumab/ipilimumab group vs 15% in the sunitinib group. A 30% or greater reduction in target kidney lesion(s) was observed in 35% of patients receiving the combination treatment vs 20% in patients receiving sunitinib.

Treatment-related adverse events of any grade occurred in 94% of patients receiving combination treatment and 97.0% of patients receiving sunitinib, and no new safety signals emerged over the longer follow-up.

“We have now evaluated Opdivo plus Yervoy in multi-year phase 3 trials across RCC, melanoma, non-small cell lung cancer, and mesothelioma, and in all of these studies, we have seen improved survival compared to the existing standard of care,” said Nick Botwood, MD, vice president, interim head, Oncology Development, Bristol Myers Squibb, in a press release. “The 4-year results from CheckMate -214 build on our understanding of and leadership in addressing advanced RCC, reinforcing the potential for durable, long-term survival benefits with Opdivo plus Yervoy in the first-line setting. Taken as a whole, these data provide further evidence for the value of distinct but complementary dual checkpoint inhibition in the treatment of advanced cancers.”

References
1. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma 711P in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 711P.
2. Bristol Myers Squibb. Four-year data continue to show superior, long-term survival benefit with Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma. Press release. September 17, 2020. Accessed September 18, 2020. https://bit.ly/3mCwhwO.


The combination use of nivolumab plus ipilimumab, compared with sunitinib, continued to show benefit during a 4-year follow-up in patients with advanced renal cell carcinoma.

Ipi-Nivo Combination Yields Improved Responses After 4-Year Follow-Up in Advanced RCC

Atezolizumab (Tecentriq) increased the pathological complete response (pCR) by 10% or more in “immune-rich” groups with high-risk and locally advanced triple-negative breast cancer (TNBC), according to data from the phase 3 NeoTRIPaPDL1 trial presented at the 2020 ESMO Virtual Meeting.1

Moreover, the agent also turned PD-L1 negative tumors positive in most immunotherapy-treated patients. However, atezolizumab did not improve pCR when added to carboplatin and nab-paclitaxel (Abraxane).

“PD-L1 expression was significantly associated with pCR, which increased with higher PD-L1 expression on immune cells,” said Giampaolo Bianchini, an author of the NeoTRIPaPDL1 study (NCT02620280) who presented the findings.

The pCR with atezolizumab was highest in the study’s “immune-rich” groups, defined as patients with PD-L1–positive immune cells (PDL1 IC+), or stromal tumor-infiltrating lymphocyte (sTILs) or intermediate/high intratumoral TILs (iTILs).1 Data showed that the pCR with the atezolizumab-containing regimen was 86.9% versus 72.0% with chemotherapy alone in patients with IC2/3 (PD-L1 expression of ≥ 5%; Δ + 14.96%) and 56.2% versus 44.0% in patients with IC1 (PD-L1 ≥ 1% and < 5%; Δ + 12.25%). A pCR benefit was not seen in patients with PD-L1 expression of less than 1% (IC0), where chemotherapy alone led to a higher pCR than the immune checkpoint inhibitor (ICI)-based combination (41.07% vs 35.09%) with a Delta that favored chemotherapy by 5.9%. The P value for this test for interaction, which measured log PD-L1 IC to correct skewness, was .02.

The overall pCR rates between treatment arms were 52.3% with atezolizumab and 47.7% with chemotherapy (P = .46; Δ 4.62%).1

The NeoTRIPaPDL1 trial tested the addition of atezolizumab to nab-paclitaxel in 280 women with high-risk (T1cN1; T2N1; and T3N0) and locally advanced TNBC versus carboplatin and nab-paclitaxel alone. After completing 8 cycles of either regimen, all patients in this intention-to-treat population underwent definite surgery. Investigators collected samples from all 260 patients evaluable for pCR response in the per-protocol population at baseline to assess sTILs, iTILs, and PD-L1 expression on ICs and tumor cells (TCs), and their dynamics and association with pCR. The objective of the analysis was to validate the presence of 40% or more sTILs following 1 cycle of treatment on day 1 of cycle 2 (d1c2), as predictive of pCR. Notably, d1c2 served as an early surrogate of pCR.

PD-L1 expression on ICs and TCs was measured using Roche’s VENTANA PD-L1 (SP142) Assay. Baseline patient samples amassed from the 260 patients evaluable for pCR indicated that PD-L1 IC was balanced across all 3 expression groups. The percentages of patients with IC0, IC1, and IC2/3 in the atezolizumab and chemotherapy-only arms, respectively, were 44.53% versus 42.75%; 37.50% versus 38.17%, and 17.97% versus 19.08%.

However, both sTILs (Wilcoxon, P = .046) and iTILs (Wilcoxon, P = .005) were disproportionately higher in the arm that received carboplatin and nab-paclitaxel. This “significant imbalance” in sTILs and iTILs could be responsible for the smaller differences in pCR seen between arms, said Bianchini, head of the Breast Cancer Group in the department of Medical Oncology and head of the translational and immunotherapy research group at the IRCCS Ospedale San Raffaele in Milan, Italy.

Samples collected on d1c2 additionally demonstrated that in both treatment arms, sTILs observed on d1c2 were more informative than baseline sTILs and ΔTILs and were predictive of pCR. “The majority of patients demonstrated a robust increase of TILs after 1 cycle, which was similar among arms, suggesting that [this increase] is mostly driven by chemotherapy,” Bianchini said.

At d1c2, 33.7% of patients met or exceeded 40% sTILs in the general population. In the atezolizumab group, patients who had a 40% or higher percentage of sTILs (n = 21) had a pCR of 71.4% compared with 28.0% who did not meet this threshold (n = 56). The odds ratio (OR) was 6.83 (95% CI, 2.24-20.87; P = .0007).

Among patients receiving chemotherapy alone, a 40% or greater percentage of sTILs translated to a pCR of 63.16% in the 38 patients who met or surpassed this sTIL threshold and a pCR of 33.9% in the 59 patients who did not (OR, 3.34; 95% CI, 1.43-7.83; P = .0055).

Rates of tumor absence measured on d1c2 may also be predicative of pCR. “Following the biopsy on day 1, cycle 2, tumor cells were not found in almost 1 out of 3 samples in the atezolizumab arm, which was double the observed rate in the chemotherapy arm,” said Bianchini. Specifically, no tumor cells were observed in 32.6% of patients treated with atezolizumab versus 15.65% of patients treated with chemotherapy.

At d1c2 evaluation, 37 patients in the atezolizumab group had no tumor cells and 77 patients. had observed tumor cells. The resulting in a pCR rates were 78.3% and 38.9%, respectively (P = .0002). Eighteen patients in the chemotherapy arm showed no signs of a tumor whereas 97 did. The pCR rate was consequently higher in patients with absent tumor (77.7% vs 45.3%; P = .023).

PD-L1 dynamics from baseline to d1c2 were “strong and divergent by arm of therapy.” A key finding of this analysis was that atezolizumab turned most PD-L1–negative tumors positive. “Notably, 2 out of 3 PD-L1–negative tumors converted to [PD-L1–]positive tumors in the atezolizumab arm,” Bianchi said. In total, PD-L1 IC+ rose from 45.4% (IC1, 32.0% and IC2/3, 13.3%, respectively) to 74.6% (IC1, 9.3% and IHC2/3, 65.3%, respectively). At baseline, 54.7% of patients in the atezolizumab arm were IC0, compared with 25.3% at d1c2. “PD-L1 expression in immune cells strongly increased, suggesting that this is a factor activation driven by atezolizumab,” he added.

An overall decrease in PD-L1 positivity was observed in the chemotherapy-only arm, where PD-L1 IC+ fell from 52.1% (IC1, 38.4% and IC2/3, 13.7%, respectively) at baseline to 37.9% (IC1, 23.2% and IC2/3, 14.7%, respectively). At enrollment, 47.4% of patients were PD-L1–negative. This number increased to 62.1% at d1c2.

In early-stage TNBC, administering an ICI in combination with standard neoadjuvant chemotherapy is hypothesized to improve efficacy by decreasing tumor associated macrophages and increasing TILs. TNBC is an aggressive form of breast cancer associated with poor outcomes, due largely to the paucity

of effective targeted therapies. Immunotherapy-based combinations have been recognized for their ability to significantly increase pCR in TNBC, where checkpoint inhibitor-driven spikes in TILs are associated with elevated pCR.2

Although data from Bianchini et al’s analysis of TILs, PD-L1 expression, and the dynamics of their intersection in the NeoTRIPaPDL1 per-protocol population provide insight on the interaction of immunotherapy and chemotherapy in this high-risk setting, monoclonal antibody use in this space remains opaque. This is in part due to discordance in results from various neoadjuvant studies in TNBC, with conflicting results seen in NeoTRIPaPDL1, the phase 3 KEYNOTE-522 (NCT03036488) and IMpassion031 trials (NCT03197935), and the phase 2 GeparNUEVO study (NCT02685059).

To date, KEYNOTE-522 is the largest trial to evaluate immunotherapy-containing neoadjuvant chemotherapy in TNBC. Findings from the evaluation demonstrated a “significantly higher” pCR rate among patients receiving pembrolizumab (Keytruda) with pre-operative chemotherapy versus chemotherapy alone.3 This trend was also apparent in the IMpassion031 study, where atezolizumab and chemotherapy outperformed chemotherapy alone in patients with early TNBC. A statistically significant, clinically meaningful improvement in pCR was seen with the multi-class regimen, causing IMpassion031 to meet its primary end point.4

Conversely, in the GeparNUEVO study, patients with metastatic TNBC who were treated with neoadjuvant durvalumab (Imfinzi) and nab-paclitaxel achieved a higher, but not statistically significant pCR compared with patients who only received nab-paclitaxel.5 Hope S. Rugo, MD, FASCO, called the findings from these 4 investigations “perplexing” and posited that this observed discordance signifies that the field of TNBC must continue its efforts to “understand which patients benefit from immunotherapy” in her invited discussant session.6

Bianchini G. Tumour infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020. LBA13.

Lee JS, Yost SE, Yuan Y. Neoadjuvant treatment for triple negative breast cancer: recent progresses and challenges. Cancers (Basel). 2020;12(6):1404. doi:10.3390/cancers12061404

Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

Roche’s Tecentriq in combination with chemotherapy (including Abraxane) meets primary endpoint of improved pathological complete response, regardless of PD-L1 status, as initial treatment for people with early triple-negative breast cancer. News release. Roche. June 18, 2020. Accessed September 19, 2020. https://www.roche.com/media/releases/med-cor-2020-06-18.htm

Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30(8):1279-1288. doi:10.1093/annonc/mdz158

Rugo HS. Predicting benefit from neoadjuvant therapy. Discussion presented at: 2020 European Society for Clinical Oncology Virtual Congress.; September 18-21, 2020; virtual. Presentation ID 4898.

“PD-L1 expression was significantly associated with pCR, which increased with higher PD-L1 expression on immune cells,” said Giampaolo Bianchini, an author of the NeoTRIPaPDL1 study. 

PD-L1 Expression May Be Associated with Pathological Complete Response in TNBC

The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) induced significantly improved progress-free and overall survival compared with sunitinib (Sutent) in the first-line treatment of patients with advanced renal cell carcinoma (RCC), according to the first results of the phase 3 CheckMate-9ER trial that were presented at the 2020 ESMO Virtual Congress.1

In particular, the combination led to a 49% reduction in the risk of disease progression or death, and also doubled objective response rate (ORR), compared with sunitinib (Sutent).

At a median follow-up of 18.1 months, the median progression-free survival (PFS) was 16.6 months with nivolumab/cabozantinib and 8.3 months with sunitinib (HR, 0.51; P <.0001). The combination was also found to have a manageable safety profile with a low rate of treatment-related discontinuations in patients with advanced RCC.

“With expanding options for patients with advanced RCC, the overall efficacy, safety, and quality of life benefits, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, senior physician with Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg Chair and professor of medicine with Harvard Medical School, said in a press conference during the congress. “These results, we believe, support nivolumab and cabozantinib as a potential first-line option in patients with advanced renal cell carcinoma.”

Both nivolumab and cabozantinib are currently approved in separate indications in RCC. In April 2018, the FDA approved nivolumab plus ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. Prior to that, in 2015, the PD-1 inhibitor was approved for use as a single agent in the treatment for patients with metastatic RCC following prior antiangiogenic therapy.

In 2017, cabozantinib was approved by the FDA for use in previously untreated patients with advanced RCC and was initially approved as a treatment for those who had progressed on 1 prior antiangiogenic treatment.

Previously, results of a phase 1 study showcased clinical activity with the combination of nivolumab and cabozantinib in patients with advanced genitourinary cancers;2 these data provided the rationale to study this combination in a larger trial.

In the international, randomized, phase 3 CheckMate-9ER trial, 651 patients with advanced RCC received the combination of nivolumab and cabozantinib (n = 323) or sunitinib (n = 328) in the first-line setting. Patients must have had previously untreated advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

Patients were randomized in a 1:1 fashion. In the combination arm, nivolumab was given at 240 mg intravenously every 2 weeks along with cabozantinib, which was given orally at 40 mg daily. Oral sunitinib was administered at 50 mg daily on a 4-weeks-on/2-weeks-off cycle. Treatment was administered until disease progression or unacceptable toxicity.

The primary end point of the trial was PFS, while secondary end points were OS, ORR, and safety. Health-related quality of life (HRQoL) served as an exploratory end point.

The combination demonstrated a benefit across numerous subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

Additional results showed that the median OS was not reached in either arm, leading to a 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010).

The ORR was also doubled with nivolumab/cabozantinib in this setting compared with sunitinib, at 55.7% versus 27.1%, respectively (P <.0001). In the combination arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were not evaluable or not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Moreover, 13.7% of patients had PD and 17.1% of patients were not evaluable or not assessed.

Regarding safety, the incidence of the most common, any-grade and high-grade treatment-related adverse events (TRAEs) were similar in both arms. More than 50% of patients on the combination required dose reductions of cabozantinib due to adverse effects (AEs). TRAEs led to treatment discontinuations in 15.3% of those in the nivolumab/cabozantinib arm and in 8.8% of those on sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib due to AEs, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.

The overall rate of serious AEs was similar between the 2 groups; however, liver toxicity was more common with cabozantinib/nivolumab. Nineteen percent of patients on the combination required corticosteroids due to immune-related AEs, 4% of whom needed corticosteroids for at least 30 days.

“Overall, it seems that the combination has a manageable safety profile in patients with advanced RCC,” said Choueiri.

Beyond improved treatment response and survival benefits, the combination was found to provide an improved HRQoL compared with sunitinib. HRQoL was maintained over time with nivolumab/cabozantinib versus sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy- Kidney Symptom Index (FKSI)-19 total score. The between-arm differences were significant at nearly all time points.

Disease-related symptoms (DRS) also improved with nivolumab/cabozantinib. Those who received sunitinib experienced a decline per FKSI-Disease-DRS.

Dominik Berthold, CHUV, head of the Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital in Switzerland, commented on the CheckMate-9ER trial during the press conference.

“All of this is pretty impressive,” Berthold explained. “What is the only drawback of this trial? It is probably the fact that [this combination is not] first-in-class in this equation. You have a combination of a checkpoint inhibitor and [TKI], and [already] in this indication, we have axitinib (Inlyta) and pembrolizumab (Keytruda). We also have the combination of ipilimumab and nivolumab with high response rates, and now, longer follow-up data.

“It is certainly an option for these patients,” Berthold continued. “What we still need to learn is, are there any patient populations who may benefit more from this combination than the other combinations? Cabozantinib is quite a unique TKI, which may better target [patients with] bone metastases, for example. [That is what we will need to] learn from longer follow-up.”

1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.

2. Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.J Clin Oncol. 2018;36(suppl 6):515. doi:10.1200/JCO.2018.36.6_suppl.515

“With expanding options for patients with advanced RCC, the overall efficacy, safety, and quality of life benefits, as well as individual patient characteristics, are very important considerations when you select appropriate therapy.”

Study Supports Nivolumab/Cabozantinib as Frontline Option in Advanced Renal Cell Carcinoma

Xevinapant (Debio 1143), in combination with standard cisplatin-based concomitant fractionation chemoradiation therapy (CRT) reduced the risk of mortality by half compared with CRT alone in patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN, according to updated phase 2 data presented as part of the 2020 ESMO Virtual Congress.1

“This is probably the first time in 30 years that such an overall survival benefit [has been] seen when compared to cisplatin radiotherapy in this type of cancer,” said Jean Bourhis, MD, professor in the Department of Oncology at the University of Lausanne in Switzerland. Bourhis added that these results have warranted a 5-year extended OS follow-up for the phase 2 study.

Investigators randomized 94 patients in the phase 2 portion of the study 1:1 to CRT in combination with xevinapant (n = 48) or placebo (n = 47). At median follow-up of 33 months results showed that xevinapant in combination with CRT reduced the risk of death by 51% versus placebo (HR, 0.49; 95% CI, 0.26-0.92). The updated overall survival (OS) rates were 66% (95% CI, 49%-78%) compared with 51% (95% CI, 34%-65%) in the xevinapant arm and placebo arm, respectively. Further, the median OS was not reached in the xevinapant arm versus 36.1 months in the placebo arm (95% CI, 21.8%-46.7%).1

Progression-free survival data for patients treated with xevinapant also showed statistically significant improvement over placebo, reducing the risk of disease progression or death by 66% (HR, 0.34; 95% CI, 0.17-0.68; P = .0023). The probability of PFS at 36 months was also improved to 72% compared to 36%, respectively.

The median locoregional control (LRC) was not met in either arm (HR, 0.47, 95% CI, 0.19-1.15; P = .095) and the LRC rates were 78% and 56% respectively. This improvement is in line with the 2-year analysis presented in 2019 in which the primary end point was met.

Xevinapant is a potential first-in-class oral antagonist of inhibitor of apoptosis proteins that sensitizes tumor cells to CRT by promoting programmed cell death and fostering antitumor immunity.2 Investigators hypothesized that xevinapant may optimize the efficacy of CRT as these proteins are overexpressed in squamous cell carcinoma of the head and neck.1 Improved survival and locoregional response rates suggests that xevinapant has the potential to fill an unmet need for this patient population that, despite being one of the most common malignancies worldwide, experiences relapsed disease in approximately 50% of cases.3

The FDA granted xevinapant a breakthrough therapy designation in February 2020, based on the 2-year follow-up results.2

Cisplatin CTR is associated with acute and late toxicities that are often irreversible including hearing loss and renal failure, resulting poor treatment adherence among patients.3 Overall treatment compliance for the study was comparable between the two arms. “Importantly, the addition of xevinapant resulted in a good safety profile, which did not compromise the standard of CRT delivery,” said Bourhis.

Updated safety analysis of the incidence of selected late toxicities, those occurring more than 30 days after the last administration of the investigational treatment, were also reported.

“Overall when we summarize the safety of this study, the treatment emergent adverse events [AEs] didn’t change from the 2-year analysis and regarding the late toxicity, we have a slight increase in grade 1 and 2 late toxicities reported in the xevinapant arm, but no difference in grade 3 or 4,” said Bourhis.

Rates for the incidence of any late toxicity were 50.1%, 16.7%, and 6.3%, for grades 1/2, 3, and 4, respectively, in the xevinapant arm compared with 40.4%, 17.0%, and 6.4% in the placebo arm. Specifically, the leading grade 1/2 AEs were dry mouth (25.1% vs 19.1%), dysgeusia (14.6% vs 8.5%), fibrosis (12.5% vs 8.5%), dysphagia (8.3% vs 6.4%), dysphonia (8.3% vs 14.9%), and deafness/hypoacusis (8.3% vs 8.5%).1

Grade 3 AEs in the xevinapant arm that were included in the analysis were comprised of 3 patients with dry mouth (6.3%), 2 with dysphagia (4.2%), and 1 each with dysgeusia (2.1%) or deafness (2.1%). One patient (2.1%) in the analysis was reported to have experienced grade 4 dysphagia. Comparatively, grade 3 AEs reported for the placebo arm included 3 patients with dysphagia (6.4%), 2 each with dry mouth (4.3%), dysgeusia (4.3%), deafness/hypoacusis (4.3%), and 1 with fibrosis (2.1%).1

“We can say that the safety with xevinapant was predictable and manageable without increases in severe toxicities,” Bourhis added.

Investigators will further examine event-free survival in patients with LA-SCCHN in the planned phase 3 randomized TrilynX trial (NCT04459715). An estimated 700 patients will be enrolled and randomized to CRT in combination with xevinapant or placebo for 3 cycles, followed by monotherapy with either xevinapant or placebo for 2 cycles.

1. Bourhis J, Sun XS, Le Tourneau C, et al; GORTEC Investigators. 3-year follow-up results of the double-blind, randomized phase II trial comparing concurrent high-dose cisplatin chemoradiation plus xevinapant (Debio 1143) or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. Presented at: 2020 European Society for Clinical Oncology Virtual Congress; September 19-21, 2020; virtual. LBA39.

FDA grants breakthrough therapy designation for Debiopharm’s novel chemo-radio sensitizer 2. Debio 1143 for front-line treatment of head & neck cancer. News release. Debiopharm International SA. February 27, 2020. Accessed September 19, 2020. https://bit.ly/2Vurl1x

3. Porceddu SV, Scotté F, Aapro M, et al. Treating patients with locally advanced squamous cell carcinoma of the head and neck unsuitable to receive cisplatin-based therapy. Front Oncol. 2019;9:1522. doi:10.3389/fonc.2019.01522

The first-in-class inhibitor of apoptosis protein (IAP) antagonist significantly improved overall survival in patients with LA-SCCHN.