Practice-Changing Data From 2021 Sets Tone for New Year

Virginia Kaklamani, MD

Throughout 2021, investigators of several pivotal trials presented findings that may result in shifting standards for the treatment of patients across tumor types. Published papers and presentations at several key meetings generated debates in sequencing and sparked conversations on where the next areas of opportunities exist to refine personalized therapies.

Further, as investigators announced confirmatory and preliminary findings for several trials, the FDA issued approvals that expanded the use of agents such as pembrolizumab (Keytruda) and welcomed others such as sotorasib (Lumakras) into the landscape.

The editors of OncologyLive® spoke with key opinion leaders who highlighted some of the most pivotal data that pave the way for change in the coming year.

Breast Cancer

Fam-trastuzumab deruxtecan-nxki (Enhertu) has generated buzz for close to 2 years following the landmark data from the phase 2 DESTINY-Breast01 trial (NCT03248492). These data led to the accelerated approval of the agent for patients with advanced HER2-positive metastatic breast cancer who have received 1 or more prior anti–HER2-based regimens.

At the European Society for Medical Oncology (ESMO) Annual Congress 2021, investigators further solidified the advantage of trastuzumab deruxtecan in a phase 3 study vs trastuzumab emtansine (T-DM1; Kadcyla).

“Trastuzumab deruxtecan demonstrated a highly statistically significant and clinically meaningful improvement in PFS vs T-DM1 in patients previously treated with trastuzumab and taxane for HER2-positive metastatic breast cancer,” said Virginia Kaklamani, MD. “These data confirm that trastuzumab deruxtecan is tolerable with manageable toxicity and a significant improvement in [interstitial lung disease] profile vs studies performed in more heavily pretreated patients. This study will lead to a paradigm shift in the treatment of HER2-positive metastatic breast cancer,” said Kaklamani, who is professor of medicine in the division of hematology/oncology at University of Texas (UT) Health San Antonio and is the leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center.

Patients were randomized 1:1 and the primary end point was progression-free survival (PFS) by blinded independent central review. The median PFS was not reached (95% CI, 18.5-not estimable [NE]) in the trastuzumab deruxtecan arm vs 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm (HR, 0.28; 95% CI, 0.220.37; P = 7.8 × 10-22).

Further, the estimated 12-month overall survival (OS) event rates were 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%), respectively. Similar rates of treatment-emergent adverse effects were observed, and no drug-related deaths occurred in either arm. Adjudicated drug- related ILD occurred in 10.5% of patients with trastuzumab deruxtecan vs 1.9% with T-DM1. Investigators concluded that these data present an unanswered clinical ques-tion regarding sequencing of the agent among other HER2-targeting agents.

For more from DESTINY-Breast03, visit bit.ly/3nkpslC.

Gynecologic Malignancies

Pembrolizumab (Keytruda) plus chemother-apy with or without bevacizumab (Avastin) resulted in a statistically significant and clinically meaningful improvement in OS and PFS in patients with persistent, recur-rent, or metastatic cervical cancer, according to Bradley J. Monk, MD, FACS, FACOG, who added that next steps will examine the addition of checkpoint inhibitors to chemother-apy and radiation.

Results from the phase 3 KEYNOTE-826 (NCT04221945) showed that pembrolizumab plus chemotherapy with or without beva-cizumab resulted in a median PFS of 10.4 months (95% CI, 9.1-12.1) vs 8.2 months (95% CI, 6.4-8.4) with chemother-apy with or without bevacizumab in the all-comer population (HR, 0.65; 95% CI, 0.53-0.79; P < .001). The median OS was 24.4 months (95% CI, 19.2–not reached) in the investigative arm vs 16.5 months (95% CI, 14.5-19.4) in the control arm (HR, 0.67; 95% CI, 0.54-0.84; P < .001). The agent was approved based on these data in October.

Bradley J. Monk, MD, FACS, FACOG

“[Other efforts are now adding] checkpoint inhibitors, such as pembroli-zumab, to chemotherapy and radiation, [such as the] phase 3 study called KEYNOTE-818 [NCT04221945],” said Monk who is a profes-sor in the Division of Gynecologic Oncology at Arizona Oncology, University of Arizona College of Medicine, Creighton University School of Medicine at St Joseph’s Hospital; medical director of the Gynecologic Program of the US Oncology Research Network; and co-director of GOG Partners. “Hopefully, [with this approach, we will] cure more patients, which is really what we’re trying to do,” Monk said. “I like helping [patients] live longer and I like helping them feel better, but really, the goal is to cure patients which is what the other sponsor is doing with durvalumab [Imfinzi]. Two studies are now examining frontline chemotherapy and radiation.”

For more from Monk on KEYNOTE-826, visit bit.ly/3owtXZT.

GI Malignancies

The combination of nivolumab (Opdivo) and chemotherapy has shown a significant benefit across outcomes for patients with gastric cancer and results from the phase 3 CheckMate 649 trial (NCT02872116) solidified its role in the treatment paradigm. On April 16, 2021, the FDA approved the PD-1–blocking antibody in combination with fluoropyrimidine- and platinum-con-taining chemotherapy for advanced or metastatic gastric cancer, gastro-esophageal junction cancer (GEJC), and esophageal adenocarcinoma.

Data from the trial showed that patients treated with the combination of nivolumab and either FOLFOX (folinic acid, fluoroura-cil and oxaliplatin) or CapeOX (capecitabine plus oxaliplatin) chemother-apy achieved a median OS of 13.8 months (95% CI, 12.6-14.6) in 789 patients, compared with 11.6 months (95% CI, 10.9-12.5) in 792 patients treated with chemo-therapy alone (P = .0002). The overall response rates were 47% (95% CI, 43%-50%) vs 37% (95% CI, 34%-40%), respectively.

Jaffer A. Ajani, MD

“Incidentally, this was not the primary end point of this study when it was initially designed; this was [adjusted] during the study as more data came in. The primary end point is PFS and OS for CPS 5 or higher. There were 2 other groups: CPS 1 to 4 and all patients,” said Jaffer A. Ajani, MD, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “There were a series of prior studies before this which already demonstrated that PD-L1 expression makes a difference. If [a patient is] PD-L1 positive, irrespective of the number, it makes a differ-ence. Looking at the survival curves, there is benefit [seen across groups] and the maxi-mum benefit was for those with CPS of 5 or higher for PFS and OS; this was a consider-able benefit. The median survival difference was more than 3 months. You don’t get that with gastric cancer very often, and PFS is approximately 1.6 months. The P values are very strong. [These data] have been practice changing. There are further studies that are looking to see if that space can be further elaborated on, but the best evidence we have right now [for this combination] is from CheckMate 649.”

For more on CheckMate 649, visit bit.ly/3kJTnSF.

Prostate Cancer

Radiopharmaceuticals are making headway as treatment options in metastatic castra-tion-resistant prostate cancer (mCRPC) with lutetium 177 (177Lu)–PSMA-617 leading the pack in 2021.

Findings from the phase 3 VISION trial (NCT03511664) showed that at a median follow-up of 20.9 months, the addition of ¹⁷⁷Lu PSM617 the median OS was 15.3 months in the investigative arm vs 11.3 months in the standard-of-care arm (HR, 0.62; 95% CI, 0.52-0.74; P < .001). The radiographic PFS was 8.7 vs 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P < .001).

Neal Shore, MD

“This study involved patients who had mCRPC who had progressed on at least 1 novel hormonal agent, and at least 1 taxane-based therapy,” said Neal Shore, MD, US Chief Medical Officer of Surgery and Oncology at GenesisCare USA, and director at Carolina Urologic Research Center in Myrtle Beach, South Carolina. “Many of these patients had had multiple taxane therapies and multiple novel hormonal agents. These patients had high tumor burden [and] had progressed on numerous lines of therapy yet were highly motivated to be randomized to receive ¹⁷⁷Lu-PSMA-617.”

“The VISION trial wonderfully demonstrated the benefit of delaying disease progression by rPFS monitoring, as well as an HR and a survival benefit of approximately 0.6, which is important because its unique mechanism of action supplements the already approved unique mechanisms of action of androgen receptor pathway inhibitory drugs, taxanes, other radiopharmaceuticals such as radium-223 dichloride [Xofigo], and even immunotherapeutics. This is extremely important. This study will clearly lead to additional trials, looking in the prechemotherapy mCRPC and metastatic castration-sensitive prostate cancer populations. Assuredly, there will be other radioisotopes that can be linked to antibodies that will add to the opportunities for trials, research, and therapeutic awareness throughout the prostate cancer journey.”

In September, the FDA granted priority review to the application for ¹⁷⁷Lu-PSMA-617.

For more on the VISION trial, visit bit.ly/3l2DzL9.

Lung Cancer

Results of IMpower010 (NCT02486718), presented at several meetings and most recently published in the Lancet, generated discussions on the role of adjuvant atezolizumab (Tecentriq) over best supportive care for patients with non–small cell lung cancer (NSCLC), specifically in those with earlier-stage disease (IB-IIIA). Improved disease-free survival (DFS) data suggest that patients treated with adjuvant atezolizumab after adjuvant chemotherapy with PD-L1 expression greater than 1%.

At a median follow-up of 32.8 months, the median DFS for those who had received atezolizumab was NE (95% CI, 36.1-NE) compared with 35.3 months (95% CI, 29.0-NE) in those who received best supportive care (HR, 0.66; 95% CI, 0.50-0.88; P = .004). The benefit was extended to all randomized patients in the intention-to-treat population. The median DFS for those in the atezolizumab arm was NE (95% CI, 36.1-NE) vs 37.2 months (95% CI, 31.6-NE) in the best supportive care arm (HR, 0.81; 95% CI, 0.67-0.99; P = .04).

Stephen V. Liu, MD

“Looking at immunotherapy for patients with completely resected NSCLC after chemotherapy and immunotherapy has been a transformative treatment for metastatic lung cancer,” said Stephen V. Liu, MD. “We also know that for patients with resected lung cancer, while our goal is cure, it’s not always our expectation. Lung cancer is a very difficult disease to eradicate.” Liu is an associate professor of medicine, director of thoracic oncology and director of developmental therapeutics at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC.

The relapse rate for patients treated with curative intent is approximately 60%, and for those treated earlier in their disease course, immunotherapy may reduce incidence of recurrence. “Implementing immunotherapy in that setting really can improve our outcomes and extend the cure to more people coupled with earlier detection and screening,” Liu said. “I think this has a chance to make a huge impact for patients with lung cancer.”

The FDA approved adjuvant atezolizumab following resection and platinum-based chemotherapy for patients with stage II to IIIA disease with a PD-L1 expression of at least 1% in October.

For more on IMpower010, visit bit.ly/3wU1vol.

Hematologic Malignancies

Approvals in hematologic malignancies for the 2021 calendar year included the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (Tecartus) for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Data from the phase 2 ZUMA-3 trial (NCT02614066) presented at the 2021 American Society of Clinical Oncology Annual Meeting and later published in The Lancet, showed that treatment with the product elicited complete remission (CR) or complete remission with incomplete hematological recovery (CRi) among 70.9% of treated patients. This included a CR rate of 56.4%. As of the data cutoff, 31% of patients who achieved a CR/CRi were in ongoing remission without subsequent allogeneic stem cell transplant.

The median duration of response with censoring at subsequent allogeneic stem cell transplant, relapse-free survival, and overall survival (OS) was 12.8 months (95% CI, 8.7-NE), 11.6 months (95% CI, 2.7-15.5), and 18.2 months (95% CI, 15.9-NE), respectively. The median OS was not reached in patients who achieved CR/CRi with the CAR T-cell therapy.

Bijal Shah, MD, MS

“The [reported] median OS was outstanding; 18.2 months for the group,” said Bijal Shah, MD, MS, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida. “In those who achieved a CR or CRi, we haven’t yet reached median survival estimate. For the types of patients we enrolled, recognizing many had seen prior inotuzumab ozogamicin (Besponsa) or prior blinatumomab (Blincyto), transplant and the like, these data are quite remarkable.”

“The [reported] median OS was outstanding; 18.2 months for the group,” said Bijal Shah, MD, MS, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida. “In those who achieved a CR or CRi, we haven’t yet reached median survival estimate. For the types of patients we enrolled, recognizing many had seen prior inotuzumab ozogamicin (Besponsa) or prior blinatumomab (Blincyto), transplant and the like, these data are quite remarkable.”

For more on the approval of brexucabtagene autoleucel, visit bit.ly/3COQmrl.