‘Monumental’ and ‘highly meaningful’ advances across solid tumors highlight ESMO program
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MADRID — Remarkable. Highly meaningful. Monumental.
These are just a sampling of adjectives used to describe late-breaking abstracts presented during presidential symposium sessions at this year’s ESMO Congress.
Multiple studies highlighted potential new standards that may provide clinically meaningful benefits to patients, according to investigators and key opinion leaders who were not involved with the research.
This Healio exclusive highlights three of those abstracts — spanning urothelial cancer, lung cancer and colorectal cancer — that have the potential to change practice.
‘Big breakthrough’ in urothelial cancer
A two-drug combination improved outcomes compared with first-line chemotherapy for adults with locally advanced or metastatic urothelial carcinoma.
The randomized phase 3 KEYNOTE-A39/EV-302 trial met its dual primary endpoints, showing the combination of pembrolizumab (Keytruda, Merck) and enfortumab vedotin-eifv (Padcev; Seagen, Astellas Pharma) nearly doubled OS and PFS among patients with previously untreated disease who were eligible for cisplatin- or carboplatin-containing chemotherapy.
The findings — which prompted a 20-second ovation from in-person ESMO attendees — support the combination as a potential new standard for first-line treatment of this population, according to investigators.
"There’s no doubt that this is really a big breakthrough in our treatment paradigm," researcher Shilpa Gupta, MD, director of genitourinary medical oncology at Taussig Cancer Institute and co-leader of the genitourinary oncology program at Cleveland Clinic, told Healio | HemOnc Today. "We saw remarkable efficacy with this combination."
Platinum-based chemotherapy has been standard first-line treatment for locally advanced or metastatic urothelial carcinoma for more than 30 years, Gupta said. Cisplatin-based chemotherapy has been preferred; however, more than half of patients cannot receive cisplatin due to age, comorbidities, performance status or other factors.
Median survival has ranged from 12 to 14 months for a generation, according to investigators.
“Improving outcomes with frontline therapy has remained a huge unmet need,” Gupta said.
The FDA previously granted accelerated approval to pembrolizumab — a PD-1 inhibitor — in combination with the antibody-drug conjugate enfortumab vedotin as first-line treatment for cisplatin-ineligible adults with locally advanced or metastatic urothelial carcinoma.
The global, open-label KEYNOTE-A39/EV-302 trial served as the confirmatory trial to support the accelerated approval.
The trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma regardless of PD-L1 expression or cisplatin eligibility.
Researchers assigned 442 patients to 3-week cycles of enfortumab vedotin 1.25 mg/kg via IV on days 1 and 8, with pembrolizumab dosed at 200 mg IV on day 1. Protocol specified a maximum 35 cycles for pembrolizumab but no maximum for enfortumab vedotin. The other 444 patients received gemcitabine with cisplatin or carboplatin for up to six cycles. Treatment continued until disease progression, clinical progression, unacceptable toxicity or maximum cycles.
PFS per blinded independent central review and OS served as dual primary endpoints. Secondary endpoints included overall response rate and safety.
Results showed the enfortumab vedotin-pembrolizumab combination significantly prolonged PFS (median, 12.5 months vs. 6.3 months; HR = 0.45; 95% CI, 0.38-0.54) and OS (median, 31.5 months vs. 16.1 months; HR = 0.47; 95% CI, 0.38-0.58).
The OS benefit appeared consistent regardless of cisplatin eligibility (eligible, HR = 0.53; 95% CI, 0.39-0.72; ineligible, HR = 0.43; 95% CI, 0.31-0.59), PD-L1 expression (high, HR = 0.49; 95% CI, 0.37-0.66; low, HR = 0.44; 95% CI, 0.31-0.61) and other prespecified factors.
Researchers also reported a higher confirmed ORR (67.7% vs. 44.4%; P < .00001) and a higher complete response rate 29.1% vs. 12.5%) in the combination group.
Fifty percent of patients assigned the combination developed peripheral sensory neuropathy, and more than one-third developed pruritus (39.8%), alopecia (33.2%) or maculopapular rash (32.7%).
Four treatment-related deaths occurred in each treatment group. Deaths in the combination group were due to asthenia, diarrhea, immune-mediated lung disease and multiple organ dysfunction syndrome.
Grade 3 or higher treatment-related adverse events occurred among 55.9% of patients assigned the combination and 69.5% of those assigned chemotherapy. Such events in the combination arm included skin reactions (15.5%), peripheral neuropathy (6.8%) and hyperglycemia (6.1%).
"Peripheral neuropathy is not something minimal that just goes away," Gupta said. "It can be cumulative and can become crippling, so we have to be really cognizant about timely dose reductions or withholding doses if we want to maintain our patients on this regimen."
Andrea B. Apolo, MD, senior investigator in NCI’s Genitourinary Malignancies Branch and head of the bladder cancer section, called the results “monumental for [the] field.”
“We welcome a new standard of care in the management of advanced/metastatic urothelial carcinoma, but with new standards of care come questions and challenges,” Apolo said.
Those questions, Apolo said, include: What is the best second-line therapy? Is there a role for immune checkpoint inhibition after enfortumab vedotin-pembrolizumab? How can toxicity with the combination be reduced? What is the efficacy of enfortumab vedotin-pembrolizumab in earlier states of disease, such as muscle invasive and nonmuscle invasive?
“And we must discuss the cost,” Apolo said. “Enfortumab vedotin-pembrolizumab is expensive. Will patients, insurance and public systems be able to afford this treatment?”
Despite uncertainty in those aeras, “the future looks bright” for patients, Apolo said.
“[This combination] has raised the bar for OS in metastatic urothelial carcinoma,” she said.
New option in resectable lung cancer
The addition of nivolumab (Opdivo, Bristol Myers Squibb) to neoadjuvant chemotherapy, followed by adjuvant nivolumab, improved outcomes for patients with untreated resectable non-small cell lung cancer, randomized phase 3 study results showed.
The combination prolonged EFS, and the findings support perioperative nivolumab as a potential new treatment option for patients with resectable NSCLC, according to Tina Cascone, MD, PhD, associate professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center.
“I’m very encouraged by the results, which were statistically significant and clinically meaningful,” Cascone told Healio | HemOnc Today. “I look forward to seeing how the data evolve as they mature, including with regard to overall survival.”
Anywhere from 35% to 60% of patients with resectable NSCLC treated with surgery alone experience relapse, Cascone said. Adding platinum-based chemotherapy in the neoadjuvant or adjuvant settings only improves survival by a few percentage points, and it also adds to toxicity, she said.
Although nivolumab with chemotherapy has become standard neoadjuvant treatment for eligible patients with resectable NSCLC, no phase 3 studies had evaluated the efficacy of perioperative nivolumab-chemotherapy treatment.
The double-blind CheckMate 77T trial included 461 adults with resectable stage II to stage IIIB NSCLC. All patients had EGFR/ALK wild-type disease and ECOG performance status of 0 or 1.
Researchers assigned 229 patients to neoadjuvant treatment with 360 mg nivolumab every 3 weeks plus platinum doublet chemotherapy for four cycles, followed by surgery, followed by adjuvant therapy with 480 mg nivolumab every 4 weeks for up to 1 year. The other 232 patients received placebo plus neoadjuvant chemotherapy, followed by surgery, followed by placebo.
EFS served as the primary endpoint. Secondary endpoints included pathologic complete response and major pathologic response — both assessed by blinded independent review — as well as OS and safety.
A prespecified interim analysis performed after minimum follow-up of 15.7 months showed the study met its primary endpoint, demonstrating improved EFS in the nivolumab group (median, not reached vs. 18.4 months; HR = 0.58; 97.36% CI, 0.42-0.81).
The EFS benefit persisted regardless of disease stage (stage II, HR = 0.81; 95% CI, 0.46-1.43; stage III, HR = 0.51; 95% CI, 0.36-0.72), nodal status and tumor histology. Nivolumab improved EFS among patients with PD-L1 expression less than 1% (HR = 0.73; 95% CI, 0.47-1.15), with a more profound benefit among those with PD-L1 expression of 1% or more (HR = 0.52; 95% CI, 0.35-0.78).
Researchers also reported higher rates of pathologic complete response (25.3% vs. 4.7%; OR = 6.64; 95% CI, 3.4-12.97) and major pathologic response (35.4% vs. 12.1%; OR = 4.01; 95% CI, 2.48-6.49) in the nivolumab group.
A similar percentage of patients in the nivolumab and placebo groups experienced grade 3/grade 4 treatment-related adverse events (32% vs. 25%) and surgery-related adverse events (12% each).
Marina Chiara Garassino, MD, professor of medicine at The University of Chicago, called the HR for EFS “impressive.” However, she said several questions remain.
“Are all perioperative combinations similar in terms of efficacy? The answer, I think, is yes,” Garassino said. “Should we treat patients with PD-L1-negative status? Data from prior trials suggest the answer is yes. ... The big question is whether perioperative therapy is superior to neoadjuvant only. I don’t think we really know.
“We do know patients who achieved a complete pathologic response do very well,” Garassino added. “For those who do not achieve a complete pathologic response, we have to work with new biomarkers, circulating tumor DNA and new drugs, and we have to run proper trials to raise the bar for these patients which, unfortunately, is still very low.”
Cascone agreed patient selection will be key moving forward.
“Our goal now is to try to identify the population of patients with specific characteristics that can help identify who merits continuation of therapy in the adjuvant setting, who can be treated with a neoadjuvant immune-based approach only, and those who perhaps need intensification of care in the adjuvant setting,” Cascone said.
‘Meaningful’ advance in colorectal cancer
Sotorasib (Lumakras, Amgen) plus panitumumab (Vectibix, Amgen) prolonged PFS compared with standard of care for patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer, study results showed.
The combination also conferred benefit with regard to response rate, response duration and disease control, according to the findings, published simultaneously in The New England Journal of Medicine.
“In my opinion, [this trial establishes this regimen] as the new standard third-line therapy for KRAS G12C mutated metastatic colorectal cancer,” researcher Marwan Fakih, MD, medical oncologist and professor in the department of medical oncology and therapeutics research at City of Hope, told Healio | HemOnc Today. “The combination has also been shown previously to be safe when combined with FOLFIRI and has been associated with robust activity in this population. That data provides further rationale to moving sotorasib [and] panitumumab in combination with systemic chemotherapy in earlier lines of treatment.”
KRAS G12C mutations are present in 3% to 4% of metastatic colorectal cancers. Monotherapy with KRAS G12C inhibitors has demonstrated only modest benefit, according to study background.
Fakih and colleagues conducted the randomized phase 3 CodeBreaK 300 study to assess whether combining sotorasib — a KRAS G12C inhibitor — and panitumumab, a fully human monoclonal anti-EGFR antibody, could improve outcomes.
The multicenter, open-label trial included 160 patients with chemorefractory metastatic colorectal cancer who had not received prior treatment with a KRAS G12C inhibitor.
Researchers assigned 53 patients to sotorasib 960 mg daily plus panitumumab 6 mg/kg IV; 53 patients to sotorasib 240 mg daily plus panitumumab 6 mg/kg IV; and 54 patients to investigator’s choice of trifluridine–tipiracil (Lonsurf; Taiho Oncology, Servier) or regorafenib (Stivarga, Bayer).
PFS by blinded independent central review served as the primary endpoint. Key secondary endpoints included OS, objective response and disease control rate.
Median follow-up was 7.8 months (range, 0.1-13.9).
The study met its primary endpoint, as both sotorasib-panitumumab combinations conferred significant PFS improvement compared with standard of care (sotorasib 960 mg, HR = 0.49; 95% CI, 0.3-0.8; sotorasib 240 mg, HR = 0.58; 95% CI, 0.36-0.93).
Researchers reported longer median PFS in both sotorasib-panitumumab groups (sotorasib 960 mg, 5.6 months; sotorasib 240 mg, 3.9 months; standard care, 2.2 months).
“These results are highly meaningful and are more than double the PFS noted with other approved agents, such trifluridine/tipiracil and regorafenib,” Fakih said. “Keep in mind that in unselected patient populations with metastatic colorectal cancer, the median PFS on second-line treatments is approximately 6 months. To see a median PFS of 5.6 months in a poor-prognosis population with KRAS G12C is welcome news to our patients.”
OS data remained immature at data cutoff.
“The study was not powered for an OS endpoint and, hence, we should not be expecting to meet that endpoint,” Fakih said. “Saying that, one can see that the OS are starting to separate in favor of sotorasib-panitumumab on the high-dose sotorasib arm. I do believe that the separation will become more meaningful as we continue to follow those patients.”
Results also showed higher ORRs (sotorasib 960 mg, 26.4%; sotorasib 240 mg, 5.7%; standard care, 0%) and a higher disease control rate (sotorasib 960 mg, 71.7%; sotorasib 240 mg, 67.9%; standard care, 46.3%) with the combination.
Median duration of response was 4.4 months in the sotorasib 960 group and not reached in in the sotorasib 240 mg group.
“Sotorasib plus panitumumab has an acceptable safety profile,” Fakih said. “Most of the side effects were related to panitumumab and were consistent with what we see with single agent p, such as rash and hypomagnesemia. Severe constitutional symptoms such as fatigue, gastrointestinal toxicities and bone marrow toxicities were rare.”
Grade 3 or higher treatment-related adverse events occurred among 35.8% of patients in the sotorasib 960 mg group, 30.2% of those in the sotorasib 240 mg group and 43.1% of those in the standard care group.
Grade 3 or higher treatment-related events reported among patients in the sotorasib 960 mg group included dermatitis acneiform (11.3%), hypomagnesemia (5.7%) and rash (5.7%). Grade 3 or higher treatment-related adverse events observed in the sotorasib 240 mg group included hypomagnesemia (7.5%) and diarrhea (5.7%).
In the standard care group, grade 3 or higher treatment-related adverse events included neutropenia (23.5%), anemia (5.9%) and hypertension (5.9%).
No fatal treatment-related adverse events occurred.
CodeBreaK 300 is the first randomized phase 3 study investigating the effect of combined KRAS G12C inhibition plus anti-EGFR therapy in pretreated metastatic colorectal cancer.
“We have seen promising results with high percentages of tumor shrinkage from baseline, and a significant benefit in PFS among heavily pretreated patients,” Miriam Koopman, MD, PhD, professor of medical oncology at University Medical Centre Utrecht in the Netherlands, said during a discussion of the abstract at ESMO. “The comparable results of the control arm of CodeBreaK 300 with previously published phase 3 studies with trifluridine–tipiracil and regorafenib support the validity of the results.”
However, because trifluridine–tipiracil plus bevacizumab (Avastin, Genentech) is the current late-line standard, a comparison between that regimen and sotorasib-panitumumab is necessary, Koopman said.
“The results for OS and quality of life will determine the use of sotorasib plus panitumumab in the standard-of-care last line for patients with KRAS G12C-mutated disease,” Koopman said. “If positive, this combination should only be used in patients meeting the eligibility criteria of CodeBreaK 300. ...
“Other studies in the first and second lines with RAS inhibitor plus anti-EGFR plus chemotherapy are ongoing,” Koopman added. “Moving to earlier lines of treatment with the combination of chemotherapy may add more benefit to our patients.” – by Mark Leiser
References:
Fakih MG, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2308795.
The following were presented at European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid:
Cascone T, et al. Abstract LBA1.
Pietrantonio F, et al. Abstract LBA10.
Powles TB, et al. Abstract LBA6.
For more information:
Tina Cascone, MD, PhD, can be reached at tcascone@mdanderson.org.
Marwan Fakih, MD, can be reached at mfakih@coh.org.
Shilpa Gupta, MD, can be reached at guptas5@ccf.org.
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