The myeloproliferative neoplasms encompass essential thrombocythaemia, polycythaemia vera, prefibrotic primary myelofibrosis, and overt primary myelofibrosis, all disorders driven by mutated haematopoietic stem cells, most commonly carrying the JAK2V617F mutation. These conditions predispose patients to life-threatening blood clots and bleeding, and conventional cytoreductive therapy has primarily aimed at reducing this thrombotic risk. Hydroxyurea has long served as the default first-line option, yet it leaves 10 to 40 percent of patients intolerant or resistant, and lingering concerns about its long-term leukemogenic potential have fuelled the search for alternatives.

Interferon alpha occupies a fundamentally different therapeutic niche. Rather than simply poisoning dividing cells, this immunomodulating agent acts directly on haematopoietic stem and progenitor cells. Animal studies have shown that interferon alpha rouses quiescent malignant stem cells from dormancy, with a striking preference for cells carrying the JAK2V617F mutation, ultimately driving the malignant clone toward functional exhaustion. This disease-modifying potential, combined with the improved tolerability conferred by pegylation, prompted Danish investigators to design DALIAH as the earliest and largest randomised trial of long-term pegylated interferon in newly diagnosed patients across all myeloproliferative neoplasm subtypes.

Between February 2012 and July 2015, the trial enrolled 206 patients, of whom 203 formed the modified intention-to-treat population. Adults with newly diagnosed or treatment-naive disease were eligible regardless of risk score, a deliberate design choice that broadened the trial beyond the high-risk patients targeted by most prior studies. Older patients, aged over sixty, were randomised among hydroxyurea, pegylated interferon alpha-2a, or pegylated interferon alpha-2b, while younger patients avoided hydroxyurea owing to its theoretical leukemogenic risk and were randomised between the two interferon formulations. The cohort comprised 73 patients with essential thrombocythaemia, 89 with polycythaemia vera, 16 with prefibrotic myelofibrosis, and 25 with overt primary myelofibrosis. The median age was 62 years, and JAK2V617F was the dominant driver mutation, present in 74 percent of participants with a median baseline variant allele frequency of 34 percent.

The primary endpoint was the rate of molecular response, defined by European LeukemiaNet criteria as a substantial or complete reduction in the JAK2V617F variant allele frequency, measured serially by quantitative polymerase chain reaction at eight time points up to 60 months. By intention-to-treat analysis, which counted patients who discontinued treatment as non-responders, molecular response rates were statistically indistinguishable between the two drugs: 23 percent in the hydroxyurea arm versus 24 percent in the interferon arm at 60 months. This apparent parity, however, masks a profound divergence revealed when the analysis was restricted to patients who remained on their assigned therapy.

Among those who stayed the course, pegylated interferon proved decisively superior from 36 months onward. At that juncture, 56 percent of interferon-treated patients had achieved a molecular response, compared with just 23 percent of those on hydroxyurea, a gap that widened to 67 percent versus 35 percent by 60 months. Three interferon-treated patients reached complete molecular remission, with the JAK2V617F mutation rendered undetectable by an assay sensitive to 0.1 percent. Moreover, patients on hydroxyurea lost their responses far more frequently, with 62 percent losing molecular response versus only 13 percent of interferon patients, a difference that proved highly significant. The kinetics told a parallel story: the median relative reduction in variant allele frequency from baseline to 60 months was 75 percent with interferon compared with only 20 percent under hydroxyurea.

On secondary endpoints, the two drugs traded advantages. Complete clinicohaematological response at 12 months was similar between groups, and by intention-to-treat analysis hydroxyurea held a modest edge at 18 months, 58 percent versus 38 percent, though per-protocol analysis later favoured interferon at 36 and 60 months. Hydroxyurea normalised blood counts faster, with haematological response reached in a median of 1.6 months versus 3.8 months for interferon, a predictable consequence of its direct cytorepressive action. Conversely, more hydroxyurea patients lost their haematological responses over time, 86 percent compared with 44 percent on interferon. Bone marrow histopathology delivered an unexpected finding: by intention-to-treat analysis, histopathological remission at 60 months favoured hydroxyurea, 18 percent versus 5 percent, though paired analyses and per-protocol comparisons blurred this difference, and the investigators caution that fibrosis grading was inconclusive in significantly more hydroxyurea patients.

Safety data underscored the trial’s central challenge. At 60 months, 60 percent of all patients had discontinued study treatment, and discontinuation was significantly more frequent with interferon at 65 percent than with hydroxyurea at 37 percent. Toxicity drove the disparity: 45 percent of interferon patients stopped treatment for adverse events, most commonly flu-like illness, injection-site irritation, fatigue, and neuropsychiatric symptoms, while only 13 percent of hydroxyurea patients discontinued for that reason. Notably, discontinuation for toxicity clustered among younger and female patients and varied dramatically between study sites, from 30 to 69 percent, leading the authors to speculate that investigator enthusiasm may have shaped dosing decisions. Yet a subgroup of patients tolerated interferon long-term, and no treatment-related events of grade 3 or higher occurred beyond 24 months among those continuing therapy.

Thrombosis, the cardinal clinical concern in these diseases, was not prevented by interferon. Nineteen major thrombotic events occurred during treatment, with a rate of 5.5 events per 100 patient-years among older interferon patients versus 2.8 per 100 patient-years with hydroxyurea, a difference lacking statistical significance but clinically noteworthy. Importantly, 68 percent of thrombotic events occurred while blood counts remained normalised and before any substantial molecular reduction, reinforcing the multifactorial nature of clotting risk in myeloproliferative neoplasms. No patient progressed to myelofibrosis, acute myeloid leukaemia, or myelodysplastic syndrome, and five deaths were recorded across the cohort without an evident treatment-related pattern.

The DALIAH results arrive amid converging evidence that molecular response is not merely a laboratory curiosity. Data from the CONTINUATION-PV and MAJIC-PV trials link deepening JAK2V617F depletion with prolonged event-free survival, suggesting that eradicating the malignant clone may genuinely alter disease course. Within this framework, interferon’s slow but sustained molecular advantage, even as hydroxyurea’s responses eroded, positions low-dose pegylated interferon alpha-2a as a viable first-line option for carefully selected patients, particularly younger individuals in whom decades of cytoreductive therapy loom ahead. The trial’s authors call for biomarkers capable of predicting both response and tolerability at diagnosis, noting that mutated DNMT3A may confer interferon resistance. They also propose an intriguing strategy: an initial six to twelve months of combination therapy using hydroxyurea to rapidly normalise counts while interferon gradually strips away the malignant clone, followed by interferon monotherapy. With pegylated interferon alpha-2b withdrawn from the European market but alpha-2a still available and mono-pegylated ropeginterferon expanding the armamentarium, the era of disease-modifying first-line therapy for myeloproliferative neoplasms may finally be within reach.

Subject of Research: A five-year randomised phase 3 trial comparing pegylated interferon alpha with hydroxyurea as first-line cytoreductive therapy in myeloproliferative neoplasms.

Article Title: Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark

Article References: Knudsen, T. A., Hansen, D. L., Ocias, L. F., Bjerrum, O. W., Brabrand, M., Christensen, S. F., Eickhardt-Dalbøge, C. S., Ellervik, C., El Fassi, D., Frederiksen, M., Kjær, L., Kristensen, T. K., Kruse, T. A., Larsen, M. K., Mourits-Andersen, T., Möller, S., Overgaard, U. M., Severinsen, M. T., Skov, V., … Hasselbalch, H. C. (2026). Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark. eClinicalMedicine, 100, Article 104193. https://doi.org/10.1016/j.eclinm.2026.104193

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104193

Keywords: myeloproliferative neoplasms, pegylated interferon alpha, hydroxyurea, JAK2V617F, molecular response, DALIAH trial, polycythaemia vera, essential thrombocythaemia, primary myelofibrosis, phase 3 trial, cytoreductive therapy, haematology

The trial enrolled 620 patients with previously untreated metastatic non-small cell lung cancer, each confirmed to have a PD-L1 tumor proportion score of at least 50 percent, a threshold that generally predicts strong responsiveness to immune checkpoint inhibitors. Patients with EGFR, ALK or ROS1 alterations were excluded, since those molecular subgroups are typically managed with targeted therapies rather than immunotherapy alone. Participants were randomized to receive either the investigational combination or pembrolizumab by itself. In the experimental arm, sacituzumab govitecan was administered at a dose of 10 mg/kg intravenously on days 1 and 8 of each cycle, alongside pembrolizumab at 200 mg on day 1 of every 21-day cycle. The study was open-label, and its dual primary endpoints were progression-free survival as assessed by blinded independent central review and overall survival.

The efficacy data revealed a pattern that has become familiar in oncology trials that miss their primary goals: encouraging numerical trends that ultimately fail the test of statistical rigor. Median progression-free survival by blinded independent central review was 11.8 months for patients receiving the combination, compared with 7.7 months for those receiving pembrolizumab alone, corresponding to a hazard ratio of 0.81 with a 95 percent confidence interval of 0.66 to 1.00 and a P value of 0.0252. Although patients on the combination lived a median of roughly four months longer without their disease progressing, the result did not cross the prespecified threshold for statistical significance that the trial design demanded.

The interim overall survival analysis was even less encouraging. Median overall survival was 21.5 months in the sacituzumab govitecan plus pembrolizumab arm versus 22.8 months with pembrolizumab alone, yielding a hazard ratio of 1.07 with a 95 percent confidence interval of 0.85 to 1.35 and a P value of 0.7155. In other words, the addition of the antibody-drug conjugate produced no survival advantage at this stage of analysis, and the point estimate actually leaned slightly in favor of monotherapy. For a field in which overall survival remains the ultimate benchmark, that finding will weigh heavily on any decision about whether the combination deserves a place in clinical practice.

Secondary measures of tumor response told a somewhat more favorable story. The confirmed objective response rate was 55.6 percent for the combination compared with 43.7 percent for pembrolizumab alone, meaning a substantially larger share of patients experienced meaningful tumor shrinkage when the antibody-drug conjugate was added. The disease control rate, reported in the study table, was 83.3 percent versus 73.1 percent, respectively. Yet the duration of those responses was nearly identical between the arms, with a median duration of response of 21.4 months for the combination and 21.3 months for pembrolizumab alone. The pattern suggests that while the combination could induce responses in more patients, it did not make the responses that occurred last any longer.

Safety findings added another layer of complexity to the interpretation. Treatment-related adverse events occurred in 93.2 percent of patients receiving the combination compared with 65.4 percent of those on pembrolizumab alone. More strikingly, grade 3 or higher treatment-related adverse events affected 55.7 percent of patients in the combination arm versus 16.5 percent in the monotherapy arm, a more than threefold increase in severe toxicity. The most common treatment-related adverse events in the combination arm included anemia, alopecia, neutropenia, diarrhea and nausea, a profile consistent with the known toxicity signature of sacituzumab govitecan. Investigators reported that the safety profile was consistent with the known profiles of the individual agents, with no new or additional toxicities observed when the two drugs were given together.

Giannis Mountzios, M.D., of the Henry Dunant Hospital Center in Athens, Greece, who presented the findings, acknowledged the tension embedded in the data. While the combination of sacituzumab govitecan and pembrolizumab produced a numerically longer progression-free survival and a higher response rate, he noted, EVOKE-03/KEYNOTE-D46 did not meet statistical significance for its primary progression-free survival endpoint, and overall survival was not significantly improved at this interim analysis. He emphasized that these findings provide important information as the field continues to evaluate treatment strategies for patients with PD-L1-high metastatic non-small cell lung cancer, framing the negative result as a contribution to knowledge rather than simply a failed experiment.

The scientific rationale behind the trial was compelling enough to justify a large Phase 3 investment. Sacituzumab govitecan links a topoisomerase I inhibitor payload to an antibody targeting TROP-2, a protein widely expressed on many epithelial cancers, including a substantial proportion of non-small cell lung tumors. The drug has already secured regulatory approvals in previously treated metastatic settings, and combining antibody-drug conjugates with immune checkpoint inhibitors has become one of the most active areas of clinical research, based on the hypothesis that chemotherapy payload-induced tumor cell death can release antigens and render tumors more visible to the immune system. Pembrolizumab, an anti-PD-1 antibody, is the established first-line standard for metastatic non-small cell lung cancer with PD-L1 tumor proportion scores of 50 percent or greater when no targetable alterations are present.

Dr. Mountzios concluded that, despite a numerical improvement in progression-free survival and a higher response rate, sacituzumab govitecan plus pembrolizumab did not meet statistical significance for progression-free survival compared with pembrolizumab monotherapy in patients with untreated PD-L1-high metastatic non-small cell lung cancer, and that overall survival also did not meet statistical significance at the interim analysis. The results leave pembrolizumab monotherapy in its longstanding position as the reference standard for this population, while raising difficult questions about whether the modest numerical gains in progression-free survival justify the substantially higher toxicity burden and the absence of any demonstrated survival benefit. For now, the trial stands as a reminder that in modern oncology, promising biology and early signals do not guarantee success when subjected to the discipline of a randomized Phase 3 test.

The International Association for the Study of Lung Cancer, founded in 1974, is the only global organization dedicated solely to the study of lung cancer and other thoracic malignancies, with a membership of more than 10,000 lung cancer specialists across all disciplines in over 100 countries. The association publishes the Journal of Thoracic Oncology and convenes the World Conference on Lung Cancer, the world’s largest meeting dedicated to lung cancer and other thoracic malignancies, which attracts nearly 7,000 researchers, physicians and specialists from more than 100 countries each year. The conference serves as the venue where pivotal trial results such as EVOKE-03/KEYNOTE-D46 are first unveiled, shaping treatment guidelines and research agendas worldwide. As the oncology community digests these findings, attention will turn to whether further analyses, biomarker-driven subgroup explorations or alternative combination strategies can eventually translate the promise of antibody-drug conjugates into durable first-line benefits for patients with advanced lung cancer.

Subject of Research: Phase 3 testing of sacituzumab govitecan plus pembrolizumab versus pembrolizumab monotherapy as first-line treatment for PD-L1-high metastatic non-small cell lung cancer

Article Title: Sacituzumab govitecan plus pembrolizumab does not meet primary endpoints in first-line PD-L1-high metastatic NSCLC

Article References: Sacituzumab govitecan plus pembrolizumab does not meet primary endpoints in first-line PD-L1-high metastatic NSCLC. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: sacituzumab govitecan, pembrolizumab, non-small cell lung cancer, PD-L1, EVOKE-03, KEYNOTE-D46, antibody-drug conjugate, immunotherapy, progression-free survival, overall survival, Phase 3 trial, IASLC

The trial’s elegant 2 × 2 factorial design addressed two independent questions simultaneously. The first randomisation, published in The Lancet, compared the four-drug PAXG regimen — cisplatin, nab-paclitaxel, capecitabine and gemcitabine — against the widely used mFOLFIRINOX combination of fluorouracil, leucovorin, irinotecan and oxaliplatin as preoperative therapy. That analysis showed PAXG produced a longer median event-free survival of 16 months versus 10.2 months, with a hazard ratio of 0.63, establishing the regimen as a new benchmark in this disease. Patients who remained free of progression or limiting toxicity after four months were then offered a second randomisation, the subject of the new analysis: whether the final two months of the same regimen should be given before surgery or reserved as adjuvant treatment after resection.

Between February 2021 and September 2024, 171 patients underwent this second randomisation, with 86 assigned to long-course and 79 to short-course preoperative chemotherapy. After central review excluded six patients found to be ineligible, the intention-to-treat population comprised 165 patients, and the final event-free survival analysis was performed after a median follow-up of 33.4 months, by which time 116 events — 70 percent of the population — had occurred. No patient was lost to follow-up, an unusually clean dataset for a trial of this size and complexity.

The primary result was unambiguous in its neutrality. Event-free survival, the prespecified primary endpoint encompassing progression, recurrence, unresectability, intraoperative metastasis detection and death, was statistically indistinguishable between the arms. The unadjusted hazard ratio comparing long-course with short-course treatment was 0.98, with a 95 percent confidence interval of 0.68 to 1.41 and a P value of 0.90. Median event-free survival was 13.0 months in the long-course group and 15.2 months in the short-course group, while three-year event-free survival rates were 27.1 percent and 23.6 percent respectively. Multivariable Cox regression confirmed the conclusion: chemotherapy duration was not associated with event-free survival after adjustment, whereas the chemotherapy regimen itself remained the only significant factor, with PAXG conferring a hazard ratio of 0.67 compared with mFOLFIRINOX.

Beneath that headline of equivalence, however, the secondary endpoints tell a more nuanced and biologically interesting story. A reduction of 50 percent or more in the tumour marker CA19-9 was achieved significantly more often with prolonged preoperative therapy, in 97 percent of evaluable patients compared with 84 percent in the short-course arm. Four complete pathological responses were observed with long-course treatment and none with short-course treatment, a borderline difference. The rate of lymph-node-negative resections was significantly higher in the long-course group, at 45 percent versus 27 percent, suggesting deeper systemic tumour clearance before the operation. Radiological partial responses were also numerically more frequent with the longer course, at 57 percent versus 47 percent.

Perhaps the most practically important finding concerns chemotherapy delivery itself. In the per-protocol population, 71 percent of patients randomised to complete all chemotherapy before surgery actually received all four planned administrations in the final phase, compared with only 51 percent of those whose last two months were deferred until after resection. Relative dose-density — the proportion of planned drug actually delivered over the final four administrations — was consistently higher across every agent in the long-course arm, with figures such as 85 percent versus 61 percent for cisplatin and 83 percent versus 54 percent for fluorouracil. The differential is almost entirely attributable to poor tolerability during the postoperative recovery period, when dose reductions and discontinuations are common. Because prior evidence has linked dose-density to overall survival in resectable pancreatic cancer, the authors argue that completing systemic therapy before surgery may be the more reliable way to deliver the full therapeutic payload.

The resection picture reinforces the message that longer preoperative therapy does not forfeit the chance of curative surgery, a concern raised by an earlier systematic review suggesting that courses of eight weeks or less yielded higher resection rates. In the CASSANDRA intention-to-treat population, 80 percent of long-course patients and 87 percent of short-course patients underwent resection, a difference that was not statistically significant. Notably, the apparent short-course advantage was concentrated among patients treated with mFOLFIRINOX, where the resection gap reached statistical significance, while the difference was negligible in the PAXG stratum — an observation the investigators interpret as evidence that more effective regimens can sustain disease control over longer preoperative periods. Concerns that prolonged neoadjuvant therapy in resectable disease simply allows tumours to progress beyond the surgeon’s reach were not supported by the data.

The trial is not without limitations, and the investigators are candid about them. The sample size for the second randomisation was constrained by the design, leaving 80 percent power only to detect large effect sizes, so smaller but clinically meaningful differences cannot be excluded. The enrolled population was necessarily selected: only patients who remained progression-free and tolerant after four months of chemotherapy could participate, limiting generalisability to all-comers. The absence of central pathological and radiological review, the inclusion of both resectable and borderline resectable disease, an upper age limit of 75 years, and the use of two different chemotherapy regimens all add interpretive complexity, although the prespecified test for a regimen-by-duration interaction was not significant. Overall survival data are also immature: with only 44 percent of deaths accrued so far, median survival was 50.5 months in the long-course arm versus 35.1 months in the short-course arm, a non-significant difference with three-year survival rates of 56.8 percent and 46.6 percent respectively — figures that, if they hold, would represent a striking improvement over historical benchmarks.

Taken together, the results reframe rather than resolve the question of neoadjuvant duration. The trial’s authors conclude that six months of preoperative chemotherapy achieves results comparable to four months before surgery with two months after, and that the choice to prolong preoperative treatment beyond four months can reasonably be personalised according to clinical circumstances, tumour biology and patient preference. PAXG emerges as the preferred backbone regimen in this setting, and patients who progress during the final two months of preoperative therapy may be spared a major operation unlikely to benefit them. The deeper biochemical, radiological and pathological responses seen with longer treatment hint at improved systemic clearance of micrometastatic disease, even if that has not yet translated into event-free or overall survival gains. What is clear is that the era of assuming a single fixed duration of preoperative therapy for all patients with operable pancreatic cancer is over, and future research must now turn toward more effective drug regimens and better tools for selecting which patients truly benefit from surgery.

Subject of Research: Optimal duration of neoadjuvant chemotherapy before surgery in resectable and borderline resectable pancreatic ductal adenocarcinoma

Article Title: Short-term versus long-course neoadjuvant chemotherapy for resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results from the second randomisation analysis of a randomised, open-label, 2 × 2 factorial phase 3 trial

Article References: Reni, M., Orsi, G., Carconi, C., Malleo, G., Procaccio, L., Macchini, M., Bencardino, K., Merelli, B., Pretta, A., Rapposelli, I. G., Pecorelli, N., Partelli, S., Sperti, E., Crippa, S., Liscia, N., Di Marco, M., Milella, M., Lonardi, S., Palumbo, D., … Falconi, M. (2026). Short-term versus long-course neoadjuvant chemotherapy for resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results from the second randomisation analysis of a randomised, open-label, 2 × 2 factorial phase 3 trial. eClinicalMedicine, 99, Article 104190. https://doi.org/10.1016/j.eclinm.2026.104190

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104190

Keywords: pancreatic cancer, neoadjuvant chemotherapy, phase 3 trial, PAXG, mFOLFIRINOX, event-free survival, CA19-9, surgical resection, dose-density, PACT-21 CASSANDRA, Short-term, versus