At this year’s European Society for Medical Oncology (ESMO) Congress, we experienced an eagerly awaited return to normality (or almost), and the quality of the science on display was anything but disappointing: from molecular medicine to treatment de-escalation, from early cancer detection and prevention to survivorship, as well as new hope and therapies for rare tumors.
NSCLC: Breaking the Code and Eco-oncology
Although KRAS has long been considered an “undruggable” target, sotorasib has emerged as the new standard of care in the second- and third-line setting for KRAS G12C–mutated non–small cell lung cancer (NSCLC). The phase III CodeBreaK 200 trial met its primary endpoint, with sotorasib doubling the progression-free survival benefit at 12 months against docetaxel, although this did not translate into an overall survival benefit; still, 34% of patients on the standard arm subsequently received a KRAS G12C inhibitor, undoubtedly influencing the overall survival outcome.1 Sotorasib will next be moving into first-line combinations, and strategies to overcome resistance will become pertinent.
GUEST EDITORS
Anna Patrikidou, MD, PhD
Karim Fizazi, MD, PhD
Dr. Patrikidou is a consultant medical oncologist at Institut Gustave Roussy. Dr. Fizazi is a medical oncologist and Head of the Department of Cancer Medicine at Institut Gustave Roussy and Professor of Oncology at the University of Paris-Saclay.
The phase II APPLE trial highlighted the value of the concept of “molecular progression” in EGFR-mutant NSCLC, not only as confirmation of disease progression and a further insight into resistance development, but as an indicator for an early switch to osimertinib from gefitinib upon detection of T790M on serial circulating tumor DNA monitoring. This strategy identified 17% of patients with molecular progression on gefitinib before progressive disease by RECIST criteria (rPD), with an 18-month overall survival of 87% vs 77% for the rPD-guided switch strategy.2 In earlier-stage NSCLC (stages II–IIIA), a consistent and meaningful improvement in disease-free survival was confirmed for osimertinib in the updated results of the ADAURA trial, which showed a 48-month disease-free survival rate of 70% vs 29% with placebo (hazard ratio [HR] = 0.23).3
Researchers presented an updated exploratory analysis of the phase III POSEIDON trial in patients with metastatic NSCLC with mutations that are considered more difficult to treat: STK11, KEAP1, and KRAS.4 Data showed that a limited course of five cycles of tremelimumab added to durvalumab plus chemotherapy extended overall survival in the study population compared with chemotherapy alone.
Undoubtedly, though, the word of the day was “molecular cancer prevention.” We learned this year from Charles Swanton, MD, PhD, that air pollution can cause several cancers5—something that we apparently knew from the 1950s, at least for lung cancer, yet somehow ignored—and can do this not via the classic mutagenic model, but rather by an inflammation-induced clonal expansion of preexisting endogenous potential driver mutations in latent cells. In other words, to prevent cancer, we may simply need not to wake up the beast—and we might also help save the planet in the process.
Genitourinary Cancers: Disappointments, Hopes, and Practicalities
In the Presidential Session, Chris C. Parker, MD, presented the results of the RADICALS-HD trial, providing much-needed data on the very practical question of the length of androgen-deprivation therapy addition to postoperative radiotherapy for prostate cancer. Although metastasis-free survival did not differ between patients who received short-term and no androgen-deprivation therapy, it differed between short- and long-term androgen-deprivation therapy (HR = 0.77, P = .03), especially for distant metastases (HR = 0.63, P = .002).6 Before we can use these data in practice, more granularity is needed in the analysis of RADICALS-HD regarding the respective benefits of long-term androgen-deprivation therapy in men with high-risk localized disease and in those with a biochemical recurrence post–local treatment (both groups were included in the trial).
In high-risk renal cell carcinoma (RCC), IMmotion010 (atezolizumab),7 CheckMate 914 (ipilimumab plus nivolumab),8 and PROSPER (nivolumab)9 reported negative outcomes, raising the count of negative adjuvant immunotherapy phase III trials to three out of four. These failures highlight the need for biomarkers that could identify patients who would benefit from such treatments.
In the first-line metastatic RCC setting, adding cabozantinib to nivolumab plus ipilimumab showed activity in progression-free survival in the phase III COSMIC-313 trial.10 This first triplet-to-doublet comparison met its primary endpoint for progression-free survival (57% vs 49% at 12 months), which was interestingly driven by the intermediate-risk rather than the poor-risk patient subgroup. However, it is probably not ready for prime time: overall survival data are lacking, and toxicity was significant (73% of patients had grade 3 or 4 adverse events, and the discontinuation rate for treatment-related adverse events was 45%).
In contrast, unprecedented responses have been observed for non–clear cell RCC subtypes with first-line pembrolizumab plus lenvatinib in the KEYNOTE-B61 trial, which resulted in a disease control rate of 79.3% and an objective response rate of 47.6%; promisingly, median duration of response was not reached at 8.2 months of follow-up.11
Finally, we must make special mention of a promising phase I trial in a rare tumor for which no drug class other than classic chemotherapy has demonstrated benefit. Testicular cancer has mored than 90% expression of the carcinoembryonic antigen claudin 6 (CLDN6). A combined chimeric antigen receptor (CAR) T cell and mRNA vaccine targeting CLDN6 showed a highly impressive objective response rate of 57% and a disease control rate of 85% at the higher dose level, with some patients showing long-term CAR T-cell persistence (> 200 days postinfusion). Treatment was well tolerated, and cytokine-release syndrome was restricted to up to grade 3, albeit frequent (45%).12 Targeting this antigen represents the most significant hope for chemotherapy-refractory germ cell tumors, which are currently lacking successful
treatment options.
Gastrointestinal Cancers: Dos and Don’ts of Immunotherapy
Colorectal cancer has been trending this year. In patients with high-risk mismatch repair–deficient stage III disease, unprecedent responses were reported after only two cycles of neoadjuvant ipilimumab plus nivolumab in the phase II NICHE-2 study.13 Major pathologic responses were observed in 95% of patients, with 67% of patients achieving pathologic complete response, and no relapses at 13 months of follow-up. Only 4% of patients experienced grade 3 or 4 adverse events. De-escalating treatment is therefore feasible if well targeted with organ-sparing approaches that minimize toxicity—detoxifying while curing.
Two phase III trials were reported in first-line metastatic/unresectable hepatocellular carcinoma with tyrosine kinase inhibitor/PD-L1 inhibitor combinations. The LEAP-002 trial did not meet its co-primary endpoints of progression-free survival and overall survival for the pembrolizumab plus lenvatinib combination.14 The camrelizumab plus rivoceranib trial, instead, was the first to report progression-free survival and overall survival benefit in unresectable hepatocellular carcinoma, with the longest reported overall survival thus far (22.1 months vs 15.2 months for sorafenib, HR = 0.62)15; however, this significance is probably partly attributed to the poor performance of sorafenib monotherapy compared with lenvatinib (19 months).
Melanoma: Refining the Face of Immunotherapy
During the Presidential Symposium this year, two studies in melanoma were presented that will undoubtedly further evolve the standard of care. The phase III SWOG S1801 trial showed superior event-free survival for combined neoadjuvant and adjuvant pembrolizumab treatment vs adjuvant treatment alone (HR = 0.58, P = .004), although the benefit was not yet seen for overall survival (HR = 0.63, P = .18).16 Of note, 6.5% vs 11% of patients experienced residual disease or developed metastasis prior to the start of adjuvant therapy in the combined vs adjuvant-alone arms. The phase II IMMUNED17 trial sent a similar message, reporting the superiority of combination adjuvant ipilimumab plus nivolumab treatment vs nivolumab alone vs placebo for recurrence-free survival (not reached vs 12.3 months vs 6.3 months, P < .0001) in stage IV melanoma without evidence of disease after radical surgery or radiotherapy, with a median follow-up of 4 years. Although not significant for median overall survival (not reached for all three arms, P = .13), the 48-month overall survival rates were markedly improved at 84% vs 73% vs 63%. Nevertheless, this was a highly selected population (> 95% of patients had fewer than three metastatic sites initially), and toxicity was not negligible (47% vs 16% of patients had grade 3 or 4 adverse events).
The star result for melanoma this year was the positive phase III tumor-infiltrating lymphocyte (TIL) therapy vs ipilimumab trial in stage IV disease,18 which is the first randomized TIL therapy trial in solid tumors. This was a strongly positive trial for progression-free survival (7.2 months vs 3.1 months, HR = 0.50, P < .001) across all subgroups; overall survival results were immature due to the short follow-up (25.8 months vs 18.9 months, HR = 0.83, P = .39), although a numerical difference in 2-year overall survival was evident (54.4% vs 44.1%). As a critique on these significant results, the comparator arm is not perfectly adapted to the current standard of care (ipilimumab plus nivolumab), and the study population was highly selected (patients had an excellent performance status and slowly progressive disease).
Desmoid Tumors: A DeFiant Newcomer in the Presidential Symposium
Finally, the first Presidential Symposium of this ESMO Congress included a hugely pleasant surprise: the phase III DeFi study provided the first solid clinical benefit data on gamma secretase inhibitors—and did so in an orphan tumor. This strategy for Notch inhibition with oral nirogacestat is the first real success story for desmoid tumors, with clear progression-free survival benefit vs placebo across all subgroups (not reached vs 15.1 months, HR = 0.29, P < .001), an impressive objective response rate of of 41% vs 8% (P < .001), and also clinically meaningful outcomes in terms of improvement in symptom severity, pain, and overall quality of life (P ≤ .007).19
DISCLOSURE: Dr. Patrikidou has served as a consultant or advisor for Basilea; and has received honoraria from Amgen, Janssen, and Merck.Dr. Fizazi has received honoraria from Astellas Pharma, Bayer, Janssen, and Sanofi; has received travel, accommodations, or expenses from Janssen and MSD; and has served as a consultant or advisor for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Curevac, ESSA, Janssen Oncology, Orion Pharma GmbH, and Sanofi.
REFERENCES
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