HYDROXYCHLOROQUINE

Hydroxychloroquine or HCQ is a long established treatment for malaria and used in auto-immune diseases such as lupus for its immune modulating actions. In cancer, it is additionally researched for its evidence on inhibiting autophagy (cellular re-cycling) which increases cancers ability to evade oncology drugs. This has shown some promise in pancreatic cancer, where autophagy can increase progression in some patients.

Some pilot trials in a variety of cancers including advanced melanoma (Highlight 1) have shown benefits when added to standard of care oncology drugs. In pancreatic cancer, tendencies to reduced progression risks have been seen in approximately half of patients lacking SMAD4 genes. About half of patients demonstrate this tumor suppressing gene is switched off by cancer activity. Another pancreatic cancer trial focused on the autophagy marker LC3-II, patients with elevated levels saw a doubling of their relative overall surivial rates with HCQ.(Highlight 2).

However, recent trials in lung cancers for the autophagy activity of HCQ have reported faster disease progression, more discontinued treatment levels. This 2025 trial reports increased side effects during lung cancer therapy and up to a fifth of patients being taken off HCQ, and the increased progression risk is reported as 17%

In palbociclib and letrozole efficacy in ER+/HER2− breast cancer treatment a recent pilot study showed some tendency to at least partial response when using HCA as for autophagy inhibition, this work is continuing and there is much more evidence needed that benefits can outweigh damaging side effects.

Most of the later stage clinical evidence shows a lack of benefit to hydroxychloroquine, including lung, pancreatic and GBM (brain) cancers. And the largest trial in GBM had better outcomes in the radiotherapy only group, though causality was not implied for the reduced survival with HCQ.

Despite the drug’s promise of killing cancer cells by blocking cellular recycling, most clinical trials using the drug have been disappointing, for instance in lung cancer. Its absolutely crucial that these drugs are recommended by your oncologist, the risks of negative impacts here are high. Only precise targeting can make HCQ useful, and then for a small number of patient groups.

Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy… This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modu...

Prognosis in pancreatic adenocarcinoma (PDA) is worsened by loss of the tumor suppressor gene SMAD4. SMAD4-deficient PDA escape radiotherapy and chemotherapy by upregulation of autophagy. In patients with SMAD4 loss, the addition of HCQ to neoadjuvant chemotherapy improved R0 resection rates and resulted in higher degree of histopathologic response. Patients with SMAD4 who received HCQ with neoadjuvant chemotherapy also displayed improved DFS and OS trends, although significance was not met. Further study of autophagy inhibition with HCQ in PDA w...

Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging..Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunoh...

The combination of concurrent and maintenance HCQ (800 mg daily) with platinum doublet chemotherapy did not improve PFS or OS outcomes for extensive-stage SCLC, resulting in more patients stopping chemotherapy early due to increased AEs. While our trial does not provide evidence for HCQ use in SCLC, its significance lies in being the third largest randomised trial of HCQ in any cancer, and the only one in lung cancer. Compared with other randomised studies of HCQ in cancer, the cumulative evidence suggests a limited role of HCQ, and possibly ev...

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URL	Rating	Highlight	Highlight 2
https://pmc.ncbi.nlm.nih.gov/articles/PMC4203514/	3.5	This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.	Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy
https://ascpt.onlinelibrary.wiley.com/doi/full/10.1111/cts.13029	3.5	DFS and OS curves for HCQ-treated patients are reported in Figures S1 and S2, respectively. There was a nonsignificant trend toward improved median OS in patients treated with HCQ with SMAD4 loss (34.43 months vs. 27.27 months, p = 0.18). There were no significant differences in DFS. Survival curves for patients treated with chemotherapy alone from the control group, stratified by SMAD4 status, are shown in Figures S3 and S4. Consistent with existing literature, SMAD4 loss in patients treated with chemotherapy alone was associated with a trend toward worse survival outcomes	Prognosis in pancreatic adenocarcinoma (PDA) is worsened by loss of the tumor suppressor gene SMAD4. SMAD4-deficient PDA escape radiotherapy and chemotherapy by upregulation of autophagy. In patients with SMAD4 loss, the addition of HCQ to neoadjuvant chemotherapy improved R0 resection rates and resulted in higher degree of histopathologic response. Patients with SMAD4 who received HCQ with neoadjuvant chemotherapy also displayed improved DFS and OS trends, although significance was not met. Further study of autophagy inhibition with HCQ in PDA with SMAD4 loss is warranted.
https://link.springer.com/article/10.1245/s10434-015-4566-4	3.5	Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens.	In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer’s dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy.
https://www.nature.com/articles/s41523-025-00722-1	3.5	Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.	Responses reported after the initial 8-week period may not be representative of the long-term activity that would be assessed in a phase II trial, but our design to limit longer-term treatment was necessary until we better understand the toxicity profile such that patients could receive standard care for their disease. Nevertheless, the combination exhibited encouraging activity, eliciting two durable PRs and 11 patients with SD that requires confirmation with a Phase II trial. The overall response rate was 2 of 7 (29%) in those with measurable disease and 8-week disease control was seen in 11 of 12 evaluable patients (92%).
https://www.nature.com/articles/s41375-019-0700-9	3	Treatment ‘successes’ was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month [myeloma] treatment ‘successes’, molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in ‘success’ rate	Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.
https://www.sciencedirect.com/science/article/pii/S0959804924017696	N/A	Combining HCQ with platinum doublet chemotherapy did not improve PFS or OS outcomes for ES-SCLC, resulting in more patients stopping chemotherapy due to increased adverse events. When considered alongside other randomised studies of HCQ in cancer, the evidence collectively indicates a limited role for HCQ as a therapeutic option.	The corresponding median OS were 8.9 and 10.2 months (HR 0.83, 95 %CI 0.48–1.45, p = 0.52). Fewer patients in the HCQ arm completed four cycles of chemotherapy due to adverse events (64 % vs. 81 %). Grade ≥ 3 adverse events were higher in the HCQ+chemotherapy arm (83.3 % vs. 27.8 %), primarily anaemia, neutropenia, and thrombocytopenia, partly due to the initially higher gemcitabine dose used
https://www.sciencedirect.com/science/article/pii/S0959804924017696	N/A	The combination of concurrent and maintenance HCQ (800 mg daily) with platinum doublet chemotherapy did not improve PFS or OS outcomes for extensive-stage SCLC, resulting in more patients stopping chemotherapy early due to increased AEs. While our trial does not provide evidence for HCQ use in SCLC, its significance lies in being the third largest randomised trial of HCQ in any cancer, and the only one in lung cancer. Compared with other randomised studies of HCQ in cancer, the cumulative evidence suggests a limited role of HCQ, and possibly even for autophagy inhibition in cancer treatment.	Notably, seven (19%) patients in the HCQ group discontinued chemotherapy early due to AEs, compared to none in the chemotherapy alone arm. We could have used a different platinum doublet, such as carboplatin and paclitaxel, [43] which is not expected to be contraindicated with HCQ. However, at the time we designed the trial, there was no evidence regarding the combination of these three agents, nor were there any randomised trials comparing first-line carboplatin-paclitaxel with standard platinum-etoposide, in contrast to carboplatin-gemcitabine
https://academic.oup.com/noa/article/2/1/vdaa046/5825547	N/A	The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2–36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6–62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3–51.7) and 29.4% (95% CI 10.7–51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3–5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation.	Because all patients received radiotherapy in our trial and adherence was high, the noticeable survival difference between the 2 groups could be due to an unexpectedly good outcome in this particular (and small) control group that was a chance finding, rather than a direct detrimental effect of hydroxychloroquine. The better performance status in patients who received radiotherapy only might also influence the difference. Alternatively, there might be some unexplained negative effect of combination therapy. However, the toxicity data do not support this, and the excess causes of deaths in the hydroxychloroquine group did indicate any obvious biologically plausible pattern.

HYDROXYCHLOROQUINE

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