Targeted Agents, Immunotherapies Are Advancing to the Adjuvant Setting in Solid Tumors

Naomi B. Haas, MD

The use of targeted therapy and immunotherapy in the adjuvant setting is emerging in several settings. After success in malignant melanoma and non–small cell lung cancer, adjuvant treatments are demonstrating improvements in disease-free survival (DFS) in other cancers, including renal cell carcinoma (RCC), esophageal/gastroesophageal cancer, and breast cancer.

Most recently, pembrolizumab (Keytruda) was granted priority review by the FDA for a new supplemental biologics license application for the adjuvant treatment of patients with RCC at intermediate- high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Extrapolating From Efficacy in Metastatic Disease

Targeted/immunotherapy in the adjuvant setting is used to treat micrometastatic disease before cancer cells become well established.

“The holy grail for any kind of cancer is a reduction in the number of recurrences and an increase in the number of patients who are completely cured of their disease [and never have a recurrence],” Naomi B. Haas, MD, said in an interview with Targeted Therapies in Oncology™. “The way we define success of adjuvant therapy or neoadjuvant therapy, however, is often based on lower bars such as improvement in DFS, defined as a delay in recurrence. That’s a pretty well-established approach in a lot of diseases [eg, breast cancer, colon cancer, lung cancer, melanoma]. A lot of us wish the bar would be a little bit higher. Sometimes it’s an improvement of only 10% or 6%, and sometimes it’s much higher than that.”

Rana R. McKay, MD

Activity in the advanced disease setting provides the rationale for investigation of these therapies in earlier disease states, said Rana R. McKay, MD, in an email correspondence with Targeted Therapies in Oncology™. “While pembrolizumab is not approved as a single agent for metastatic disease, the activity of single-agent use was demonstrated in the KEYNOTE-427 trial1 [NCT02853344] [in patients with locally advanced/metastatic RCC],” she wrote. “Additionally, the activity of single-agent nivolumab [Opdivo] has also been demonstrated for patients with metastatic disease.”

Tilting the Balance

The adoption of adjuvant targeted therapy and immunotherapy requires a balance that tilts toward benefit and quality of life over the burden of adverse events (AEs), said Haas, director of the Prostate and Kidney Cancer Program at Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania.

The best example is the exploration of adjuvant VEGF receptor tyrosine kinase inhibitors (TKIs) in the treatment of RCC, a setting in which numerous clinical trials have been conducted. The largest trial, ASSURE (ECOG-ACRIN E2805; NCT00326898),² was a 1-year blinded trial of adjuvant sorafenib (Nexavar), adjuvant sunitinib (Sutent), or 1 year of placebo. No improvement in DFS or overall survival (OS) was observed with adjuvant treatment. The ATLAS trial (NCT01599754),³ which examined the use of adjuvant axitinib (Inlyta) vs placebo for up to 3 years, was terminated early due to futility. Furthermore, adjuvant pazopanib (Votrient) did not show improvements in DFS or OS in this setting (TABLE).

Adjuvant sunitinib in the S-TRAC study (NCT00375674) showed an improvement over placebo on the end point of DFS in a more restricted high-risk clear cell RCC population, but the benefit to DFS did not translate into an OS advantage.⁴

More than 60% of patients in each of these trials had a grade 3 or 4 toxicity, and most TKI recipients required dose reductions to manage AEs. “If you’re giving a patient treatment for a year, even with sunitinib in S-TRAC, you delay recurrence by a year but the patient spent that year being miserable,” Haas said.

Based on the results from S-TRAC, sunitinib was approved by the FDA for use in the adjuvant setting. However, its use was downgraded to category 3 in the National Comprehensive Cancer Network guidelines due to a lack of OS benefit, Haas pointed out.

The data with immune checkpoint inhibitors in RCC are more exciting, Haas said. The supplemental Biologics License Application for pembrolizumab was accepted for review by the FDA on the basis of results from the KEYNOTE-564 study (NCT03142334),5 which were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.6 Adjuvant pembrolizumab induced a significant and clinically meaningful improvement in DFS compared with placebo in patients with locoregional RCC who underwent nephrectomy.

Following nephrectomy, almost half of such patients eventually have recurrence of their disease. “The data represent a paradigm shift as the first positive phase 3 study of adjuvant immunotherapy in RCC,” said McKay, a medical oncologist and associate professor of medicine at UC San Diego Health, a discussant of the ASCO session. “Ultimately, this is a quantum leap forward for our patients and provides additional options for individuals with RCC.”

KEYNOTE-564 enrolled 994 patients with histologically confirmed clear cell RCC who had undergone nephrectomy no more than 12 weeks prior to being randomized to pembrolizumab 200 mg every 3 weeks for up to 17 cycles (approximately 1 year) or placebo.

The primary end point of DFS in the intention-to- treat population favored pembrolizumab, with an HR of 0.68 (95% CI, 0.53-0.87; P = .0010). At 12 months, the DFS rates were 85.7% in the pembrolizumab arm and 76.2% in the placebo arm. DFS rates at 24 months were 77.3% and 68.1%, respectively.

The benefit favoring pembrolizumab extended to intermediate-high risk, high risk, and M1 no evidence of disease categories.

An interim OS analysis favored pembrolizumab (HR, 0.54; 95% CI, 0.30-0.96; P = .0164), with an OS rate at 12 months of 98.6% in the pembrolizumab arm and 98.0% in the placebo arm. The 24-month OS rates were 96.6% and 93.5%, respectively.

“What was really uplifting was that there was less grade 3 and grade 4 toxicity reported [compared with trials of sunitinib],” Haas said.

No new safety signals were observed with adjuvant pembrolizumab in KEYNOTE-564. Grade 3 to 5 treatment-related AEs occurred in 18.9% of patients in the pembrolizumab arm and in 1.2% in the placebo arm, with AEs leading to treatment discontinuation in 17.6% and 0.6%, respectively. There were no deaths attributed to treatment-related AEs.

Immune-mediated AEs in the pembrolizumab arm included hypothyroidism (21.1% vs 3.6% in the placebo group), hyperthyroidism (11.9% vs 0.2%, respectively), and pneumonitis (2.3% vs 1.0%).

However, the irreversible nature of some of the treatment-related AEs associated with pembrolizumab (eg, diabetes, adrenocortical insufficiency, panhypopituitarism) and\ severe AEs such as myocarditis and encephalitis could be cause for concern, Haas said, as opposed to adjuvant TKIs, with treatment- related AEs that are mostly reversible.

Given the signal for improved OS with pembrolizumab, unlike with the TKIs used in the adjuvant setting, “the results of KEYNOTE-564 are definitely going to change the way we approach adjuvant therapy for patients with RCC,” McKay said. “Use in the clinical setting is going to be dependent on multiple factors, including patients’ calculated risk of recurrence, age, comorbidities, treatment [AEs], and other variables.”

Although subset analyses demonstrated consistent benefit across all subgroups, additional studies investigating DFS by TNM stage, presence of sarcomatoid features, and other subsets are warranted, McKay said.

The FDA has set a Prescription Drug User Fee Act date of December 10, 2021, for pembrolizumab for this indication.⁵

Will Perioperative Nivolumab Be Effective in PROSPER?

The PROSPER RCC trial (NCT03055013) is a phase 3 global study sponsored by the National Cancer Institute designed to determine if perioperative nivolumab can supplant postsurgical surveillance as the standard of care in patients scheduled to undergo radical or partial nephrectomy for high-risk RCC (ie, clinical stage ≥ T2 or T_anyN+ RCC of any histology). Haas is the medical oncology study monitor for this study.

The trial is investigating immunotherapy in both neoadjuvant and adjuvant settings. Patients in PROSPER RCC assigned to the investigational arm receive a single 480-mg dose of nivolumab 7 to 28 days prior to partial or radical nephrectomy (when the study was initiated, patients received two 240-mg doses prior to surgery). Following recovery from surgery, patients then receive 9 adjuvant doses of nivolumab every 4 weeks. Those in the control arm will undergo immediate nephrectomy followed by surveillance.⁷

The nivolumab regimen was selected from findings obtained in mouse models, Haas said. “The hypothesis behind it was that you might need more tumor in place to better prime T lymphocytes to do their work,” she said. “If you give just adjuvant immune checkpoint inhibitor when there’s no cancer around, it might not be as effective. The other reason is that if you give patients treatment and then take the tumor out, you can look for pathologic complete responses, immune signatures, and the degree of tumor-infiltrating lymphocytes that are present in kidney tumor after treatment.”

She cited work from Motzer et al8 showing that clusters based on RNA print signatures can stratify patients to predict improved outcomes from VEGF inhibitors or immune checkpoint inhibitors. The 3 main types of signatures are high angiogenesis signatures that respond to antiangiogenic agents such as VEGF inhibitors, immune-mediated signatures that benefit from immune checkpoint inhibitors, and mixed signatures that may respond to both or neither.

“What we’re doing in PROSPER RCC, and I imagine will be done in some of the industry trials, is retrospectively looking at these signatures in the populations to see, based on the response, who had these signatures, who didn’t, and can we better home in on our population,” Haas said.

Adjuvant Immunotherapy in Gastroesophageal Cancer

On May 20, 2021, the FDA approved nivolumab for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy. The basis for this regulatory decision was a significant improvement in median DFS obtained with adjuvant nivolumab in the phase 3 double-blind Check-Mate 577 study (NCT02743494).^9,10

Adjuvant nivolumab doubled median DFS compared with placebo, at 22.4 months vs 11.0 months, corresponding to a 31% relative reduction in the risk of disease recurrence or death (HR, 0.69; 95% CI, 0.56-0.86; P < .001).

For patients with stage II or stage III esophageal and GEJ cancers, neoadjuvant chemotherapy followed by surgery, also called trimodality therapy, is a widely used standard of care.

“Unfortunately, risk of recurrence following trimodality therapy remains high, particularly in the 70% to 75% of patients who do not achieve a pathologic complete response,” said lead CheckMate 577 investigator Ronan J. Kelly MD, director of oncology for the Baylor Scott & White Charles A. Sammons Cancer Center in Dallas, Texas. “There is no established adjuvant treatment, with close observation as [the] standard approach. In the CheckMate 577 trial, we saw a doubling in median DFS compared [with] placebo, which suggests that [nivolumab] could become a new standard of care for these patients.”

CheckMate 577 enrolled 794 patients with stage II/III esophageal or GEJ cancer, adenocarcinoma, or squamous cell carcinoma to 240 mg of nivolumab once every 2 weeks for 16 weeks followed by 480 mg once every 4 weeks (n = 532) or placebo every 2 weeks for 16 weeks and then once every 4 weeks (n = 262) for up to 1 year. To be eligible for enrollment, patients had to have received neoadjuvant chemoradiation, undergone surgical resection, and had residual disease.

The favorable effect of nivolumab on DFS was consistent regardless of PD-L1 status, and subgroup analysis showed equal benefit in patients with stage II and III disease.

Data from an exploratory analysis in 563 patients with adenocarcinoma showed that the median DFS with nivolumab was 19.4 months vs 11.1 months with placebo (unstratified HR, 0.75; 95% CI, 0.59-0.96). Among 230 patients with squamous cell carcinoma, the median DFS with nivolumab was 29.7 months vs 11.0 months with placebo (unstratified HR, 0.61; 95% CI, 0.42-0.88).

Patient-reported quality of life was equivalent between the 2 arms, Kelly reported. “The majority of patients were not at all bothered by treatment-related [AEs] in both the nivolumab and placebo arms.” Additionally, a quality-of-life analysis showed a trend toward improvement in both arms and in maintenance quality of life after treatment was stopped, Kelly said.

Adjuvant Olaparib in Breast Cancer

In the breast cancer setting, 1 year of adjuvant treatment with the PARP inhibitor olaparib (Lynparza) following the completion of local treatment and standard adjuvant or neoadjuvant chemotherapy significantly improved both invasive DFS and distant DFS in patients with high-risk, HER2-negative, early-stage breast cancer harboring germline BRCA1/2 mutations.

Results from the OlympiA trial (NCT02032823),11 which randomized 1836 patients to continuous olaparib (300 mg twice daily) or placebo, showed that olaparib reduced the risk of invasive breast cancer recurrence, second cancers, or death by 42% (P < .0001) and the risk of distant disease recurrence or death by 43% (P < .0001) at a median follow-up of 2.5 years, reported Andrew Tutt, PhD, FMedSci, at the 2021 ASCO meeting. The study was terminated early based on a prespecified event-driven interim analysis.

The absolute difference between arms in the 3-year invasive DFS rate was 8.8 percentage points and the difference in invasive DFS in the mature cohort (median follow-up, 3.5 years) was 8.6 percentage points.

The 3-year difference between arms in distant DFS rate was 7.1 percentage points.

Fewer deaths were reported in the olaparib arm, but OS data from OlympiA are not yet mature at a median of 2.5 years. The stratified hazard ratio for death was 0.68 (P = .024) but was not significant based on a level of P < .01. The absolute different in 3-year OS rates between arms was 3.7 percentage points.

Tutt, head of the Division of Breast Cancer Research at Guy’s Hospital, King’s College, in London, England, said: “I think most of us would agree that the development of metastatic disease is a fatal event in HER2-negative breast cancer. At a median follow-up of 2.5 years, we’ve just not seen the inevitable OS events. The number of deaths was 86 in the placebo arm and 59 in the treatment arm. But the statistical boundary was incredibly rigorous at this point because we’re saving statistical power for more appropriate follow- up time points. I think that’s why it’s not statistically significant.”

Germline BRCA1 and BRCA2 sequencing “is an important biomarker in early breast cancer,” he concluded. “I think it also speaks to the need to consider genetic testing of patients in a slightly different way now. It was already beginning to be considered as a patient selection for treatment, as opposed to a risk assessment test for risk of developing BRCA-associated cancers and managing family risk.”

“I think everyone agrees that these results are practice-changing,” said Nadine Tung, MD, director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “I agree with Dr Tutt completely; we really need to get comfortable with this because it’s not just about future cancer risk at this point. It’s about optimal treatment of the cancer. At the very least, anyone who would meet the eligibility for OlympiA should be tested.”

Head and Neck: Adjuvant Pembrolizumab Being Studied

Adjuvant therapies are continuing to be investigated in more solid tumors.

The KEYNOTE-689 (NCT03765918) trial is a randomized, open-label phase 3 study evaluating pembrolizumab as neoadjuvant and adjuvant therapy to radiotherapy with or without cisplatin in the previously untreated, resectable locally advanced head and neck squamous cell carcinoma.

Patients will be randomized to neoadjuvant pembrolizumab followed by surgical resection then standard of care plus 15 cycles of adjuvant pembrolizumab or surgical resection followed by adjuvant standard of care. Dual primary end points are major pathologic response and event-free survival.

_References:

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_{2. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, phase 3 trial. Lancet. 2016;387(10032):2008-2016. doi:10.1016/S0140-6736(16)00559-6}

_{3. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol.2018;29(12):2371-2378. doi:10.1093/annonc/mdy454}

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_{5. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase III KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 18):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5}

_{6. FDA grants priority review to Merck’s supplemental biologics license application for KEYTRUDA (pembrolizumab) as adjuvant therapy in certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck; August 10, 2021. Accessed August 21, 2021. https://bit.ly/3fLSKFG}

_{7. Allaf ME, Kim SE, Master VA, et al. PROSPER: phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143). J Clin Oncol. 2021;39(suppl 15):TPS4596. doi:10.1200/JCO.2021.39.15_suppl.TPS4596}

_{8. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell. 2020;38(6):803-817.e4. doi:10.1016/j.ccell.2020.10.011}

_{9. FDA approves nivolumab for resected esophageal or GEJ cancer. FDA. May 20, 2021. Accessed August 21, 2021. https://bit.ly/2XJkVyQ}

_{10. Kelly RJ, Ajani JA, Kuzdzal J, et al; CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125}

_{11. Tutt A, Garber JE, Kaufman B, et al. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. J Clin Oncol. 2021;39(suppl 18):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1}