Anlotinib plus Tislelizumab for Recurrent Metastatic Pancreas Ductal Adenocarcinoma with Germline BRCA2 Mutation: A Case and Literature Review

doi:10.21203/rs.3.rs-3568907/v1

Download PDF

Systematic Review

Anlotinib plus Tislelizumab for Recurrent Metastatic Pancreas Ductal Adenocarcinoma with Germline BRCA2 Mutation: A Case and Literature Review

https://doi.org/10.21203/rs.3.rs-3568907/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose

While combined immunotherapy and anti-angiogenic therapy have demonstrated efficacy in renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma, the efficacy of first-line treatment for pancreatic ductal adenocarcinoma (PDAC) with germline BRCA2 mutation remains unproven.

Methods

We described a BRCA2-mutated PDAC patient who presented with posterior cardiac metastasis eight months after surgery. We performed anlotinib plus tislelizumab on him for systemic therapy.

Results

After receiving four cycles of anlotinib combined with tislelizumab, abdominal CT scans indicated a complete response. The patient sustained this response for over 13 months on the combination regimen, with no reported adverse events.

Conclusions

The combination of tislelizumab and anlotinib may offer a viable therapeutic option for recurrent metastatic BRCA2-mutated PDAC.

anlotinib

tislelizumab

pancreas ductal adenocarcinoma

BRCA2 mutation

recurrent metastatic PDAC

In 2020, pancreatic cancer (PC) resulted in 496,000 new cases and 466,000 deaths, with pancreatic ductal adenocarcinoma (PDAC) as the predominant type(Park et al. 2021, Sung et al. 2021). A majority of patients with PC are diagnosed at an advanced stage, therefore, only 20% are eligible for radical surgical resection(Versteijne et al. 2020). However, despite surgery, nearly 90% of patients experience disease recurrence within 7-9 months, leading to a 5-year overall survival (OS) rate below 10%(Rojas et al. 2023). The growing adoption of genetic testing has enabled the implementation of precision medicine(O'Reilly et al. 2020). BRCA1, BRCA2, or both (BRCA) mutations are present in 5% to 10% of familial PDAC patients and about 3% of sporadic ones(Lai et al. 2021). Such mutations can induce homologous recombination deficiency (HRD), impeding the efficient repair of double-stranded DNA breaks(Wattenberg et al. 2020). The conventional treatment for metastatic PDAC with germline BRCA mutations is platinum-based chemotherapy coupled with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor maintenance therapy(O'Reilly et al. 2020, Conroy et al. 2011, Reiss et al. 2021, Golan et al. 2019). While this regimen can enhance survival metrics, long-lasting clinical responses remain elusive, and its toxicity is noteworthy. Exploring innovative therapeutic approaches is thus essential, particularly for PDAC patients carrying BRCA2 mutations.

Research suggests that BRCA2 mutations may boost tumor cell immunogenicity and enhance responsiveness to immune checkpoint inhibitors (ICIs)(Samstein et al. 2021). Moreover, a retrospective study of metastatic pancreatic or biliary cancer with HRD demonstrated significant clinical activity of ipilimumab/nivolumab with an objective response rate (ORR) of 42% and a disease control rate (DCR) of 58%(Terrero et al. 2022). However, given the study's limited sample size, the efficacy of ipilimumab/nivolumab for BRCA2-mutated metastatic PC requires further validation. There's growing evidence that anti-angiogenic drugs can modify the tumor's immune microenvironment, potentially amplifying immunotherapy benefits(Huang et al. 2023). Such synergy has been observed in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC)(Hack et al. 2020). Additionally, several instances highlight the potential of integrating anti-angiogenic drugs with ICIs in sequential treatments for PC(Wang et al. 2022, Mafei et al. 2022). Yet, the effectiveness of this combined approach as an initial treatment for PDAC with germline BRCA2 mutations is still uncertain.

We presented a case of a patient with BRCA2 mutated PDAC who manifested metastasis in the posterior cardia eight months after surgery. The combined therapy of programmed cell death protein 1 (PD-1) inhibitor, tislelizumab, with the anti-angiogenic agent, anlotinib, exhibited notable efficacy in this patient. The patient provided written informed consent for the publication of case information and accompanying images.

A 68-year-old male with no family history presented to our hospital in August 2021, complaining of epigastric pain. An abdominal computed tomography (CT) showed a space-occupying lesion in the body of the pancreas. Preoperative carbohydrate antigen 19-9 (CA199) levels were significantly elevated at 798.7 U/mL (normal: 0-27 U/mL). On September 1, 2021, the patient underwent laparoscopic pancreatic body-tail resection and splenectomy. The postoperative pathology confirmed a diagnosis of moderately differentiated ductal adenocarcinoma (pT3N0M0) (Figure 1), and he received neither radiotherapy nor chemotherapy post-surgery. By May 2022, the patient progressed with the development of a posterior cardiac annular nodule (1.7cm × 1.3cm) (Figure 2A) with CA199, which was 35.73 U/mL (Figure 3). Despite the presence of additional lesions, the patient was merely under observation without receiving any treatment. A subsequent upper abdominal CT in August 2022 showed that the nodule had grown to 2.3cm × 2.8cm (Figure 2B), and his CA199 level spiked to 124.8 U/mL (Figure 3). Consequently, he was diagnosed with recurrent metastatic PDAC and had an Eastern Cooperative Oncology Group (ECOG) score of 1.

To uncover actionable mutations in the patient, we conducted next-generation sequencing (NGS) on both the surgical tissues and blood samples. The analysis identified a BRCA2 mutation, microsatellite stability (MSS), a tumor mutational burden (TMB) of 5.76 Muts/Mb, and PD-L1 negativity. As per the 2022 Guidelines of the Chinese Society of Clinical Oncology (CSCO) for Pancreatic Cancer and the NCCN Guidelines for Pancreatic Adenocarcinoma, Version 2, 2023, the recommended course of action was platinum-based chemotherapy. However, due to concerns regarding chemotherapy's adverse effects, the patient, in consultation with his family, opted against this treatment.

On August 30, 2022, the patient was initiated on a treatment regimen comprising anlotinib (10 mg, D1-14) and tislelizumab (200 mg, three times per week). Following 4 cycles of combination therapy, the patient achieved a complete response (CR), with total tumor disappearance (Figure 2C, D). To prevent tumor recurrence, the patient continued this regimen without any treatment-related adverse effects. At the latest follow-up in October 2023, the patient remains on this regimen. Abdominal CT scans continue to indicate CR with a progression-free survival (PFS) duration of 13 months (Figure 2E, F).

Table 1: Clinical study of pancreatic cancer with BRCA2 or BRCA1/2 mutations.
case	cancer type	mutations	age	cancer stage	lines^a	year	Current treatments	PFS (months)	OS (months)	reference
1	Pancreatic Cancer	BRCA2 mutation	64	pT3N1M0	first	2011	gemcitabine plus iniparib neoadjuvant therapy followed by surgery	32	_	(Fogelman et al. 2011)
298	ovarian cancer, breast cancer, pancreatic cancer, prostate cancer	germline BRCA1/2 mutation	29-79	advanced solid tumor	Multiple	2015	Olaparib	4.6^c	9.8^c	(Kaufman et al. 2015)
12	Pancreatic Adenocarcinoma	DNA Damage Repair Gene Mutations	45.7–74.8	metastatic	first	2018	FOLFIRINOX^b	_	14	(Sehdev et al. 2018)
154	pancreatic adenocarcinoma	germline BRCA1 or BRCA2 mutation	37–84	metastatic	first	2019	maintenance olaparib	7.4	18.9	(Golan et al. 2019)
26	pancreas ductal adenocarcinoma	germline BRCA1, BRCA2 or PALB2 mutation	41–81	locally advanced / metastatic	first or multiple	2020	platinum-based therapy	10.1	24.6	(Wattenberg et al. 2020)
_	solid cancers	homologous repair genes	_	_	_	2020	absence of progression after 6 weeks of olaparib, followed by 4 months of treatment with durvalumab + tremelimumab, then durvalumab alone for maintenance treatment	_	_	(Fumet et al. 2020)
42	Pancreatic Cancer	BRCA1, BRCA2, or PALB2	35–81	locally advanced / metastatic	first	2021	Maintenance rucaparib	13.1	23.5	(Reiss et al. 2021)

^anumber of current treatment regimens.

^bincluding oxaliplatin, irinotecan, fluorouracil and calcium folinate.

^c OS and PFS in patients with pancreatic cancer.

PDAC remains a highly aggressive and devastating disease, typically characterized by a median OS of less than 13 months in metastatic patients(Middleton et al. 2014). Posterior cardiac invasion is considered a manifestation of peritoneal metastasis, rendering surgical resection not recommended. Consequently, systemic chemotherapy is the established first-line approach for metastatic PDAC(Lellouche et al. 2021).

In this case, the application of NGS testing on the patient's blood and archived specimens revealed the presence of a BRCA2 mutation, along with negative PD-L1 expression, a low TMB, and MSS. The BRCA gene is responsible for encoding proteins involved in homologous recombination repair of double-stranded DNA breaks(Walsh 2015). Consequently, PDAC featuring a germline BRCA mutation exhibits sensitivity to platinum and PARP inhibitors(Andrei et al. 2015, Wang et al. 2020). The POLO study investigated the efficacy of maintenance olaparib in patients with platinum-sensitive metastatic PC who carried germline BRCA1 or BRCA2 mutations(Golan et al. 2019). The results showed that maintenance olaparib significantly extended PFS compared to placebo (median, 7.4 months vs. 3.8 months; P = 0.004)(Golan et al. 2019). However, there was no significant difference in median OS between the two groups (18.9 months vs. 18.1 months; P = 0.68)(Golan et al. 2019). Moreover, in this specific case, the patient and their family have adamantly declined chemotherapy. Hence, it is imperative to explore alternative chemotherapy-free treatment modalities, aiming to provide enhanced survival prospects for individuals with PDAC.

In recent years, significant attention has been dedicated to the research and development of anti-angiogenic drugs for managing PC. A phase III clinical trial demonstrated the superiority of combining erlotinib with gemcitabine compared to gemcitabine alone, as it led to notable improvements in both OS and PFS in patients with locally advanced or metastatic PC(Moore et al. 2007). However, it is noteworthy that various other anti-angiogenic drug combinations with gemcitabine have not yielded favorable outcomes concerning OS in PC patients(Van Cutsem et al. 2004, Van Cutsem et al. 2009, Kindler et al. 2010, Kindler et al. 2011, Gonçalves et al. 2012, Rougier et al. 2013, Yamaue et al. 2015, Sinn et al. 2017). These findings suggest that the utilization of anti-angiogenic drugs in conjunction with gemcitabine may have some inherent limitations in extending the OS of PC patients. Therefore, there is a pressing need to explore a new anti-angiogenic drug to improve the efficacy of PC treatment.

Anlotinib is a novel multi-targeted tyrosine kinase inhibitor renowned for its capacity to impede both tumor angiogenesis and cell proliferation(Sun et al. 2016). This therapeutic agent exhibits a broad spectrum of inhibitory effects on various critical targets, encompassing receptor tyrosine kinases such as vascular endothelial growth factor receptor 1 to 3, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 to 4, platelet-derived growth factor receptor α and β, stem cell factor receptor, and c-kit(Han et al. 2018). Clinical studies have shown that anlotinib has promising efficacy in the treatment of advanced NSCLC, small cell lung cancer, soft tissue sarcoma (STS), advanced thyroid carcinoma, and metastatic RCC(Wu et al. 2022, Shen et al. 2018). Moreover, its potential role in the context of PC has garnered substantial attention. Yang et al. found that anlotinib can induce the apoptosis of pancreatic cells both in vitro and in vivo by generating reactive oxygen species(Yang et al. 2020). Additionally, Zhang et al. shave demonstrated that anlotinib possesses the capacity to inhibit ribosomes within pancreatic cancer cells, thereby modulating various cellular functions, including the cell cycle, RNA metabolism, and lysosome(Zhang et al. 2021). In a retrospective study, the combination of anlotinib and nab-paclitaxel/gemcitabine showed a significant improvement in both PFS (5 months vs. 2.7 months, P=0.0220) and OS (9 months vs. 6 months, P=0.0060) in patients with unresectable or metastatic PDAC when compared to albumin-bound paclitaxel/gemcitabine(Wu et al. 2022). This treatment also maintained favorable tolerability profiles(Wu et al. 2022). Therefore, anlotinib is expected to be a feasible treatment modality for patients with locally advanced and metastatic PC.

Immunotherapy has revolutionized the treatment of various tumors(Timmer et al. 2021). Recent years have witnessed a notable surge in investigations into ICIs for the treatment of metastatic PC. Several studies have yielded compelling evidence suggesting that combining ICIs with chemotherapy holds promise for enhancing survival outcomes in patients with advanced PC(Zhang et al. 2022, Shui et al. 2020, Liu et al. 2022). However, it is worth noting that, except for high microsatellite instability (MSI-H) or DNA mismatch repair (dMMR), the outcomes of immunotherapy monotherapy or dual-agent immunotherapy in the context of advanced PC have often been underwhelming(Marabelle et al. 2020, Padrón et al. 2022, Feng et al. 2017, Royal et al. 2010, O'Reilly et al. 2019, Le et al. 2017). In our case, the patient was diagnosed with a BRCA2 mutation. Preclinical studies have illuminated that BRCA2 mutations could remodel the tumor microenvironment by fostering the enrichment of various immune cell populations, including T cells, natural killer cells, macrophages, and dendritic cells(Samstein et al. 2021). This, in turn, augments the anti-tumor activity of ICIs(Samstein et al. 2021). However, the patient in our case has several features that are unresponsive to ICIs, such as negative PD-L1 expression, low TMB, and MSS. Consequently, it is conceivable that immunotherapy alone may offer limited efficacy in this particular scenario.

Emerging research has shed light on the potential immunostimulatory effects of anti-angiogenic drugs and their capacity for synergistic anti-tumor action when combined with ICIs(Rini et al. 2019, Socinski et al. 2018, Motzer et al. 2019, Finn et al. 2020, Makker et al. 2019, Li et al. 2022). One notable example is the IMPOWER-150 study, which demonstrated that the addition of atezolizumab to bevacizumab, in combination with chemotherapy as a first-line treatment for metastatic NSCLC, led to improved clinical outcomes for patients, irrespective of their PD-L1 expression status or the presence of EGFR or ALK mutations(Socinski et al. 2018). In addition, Kang et al. reported a case in which the combination of pembrolizumab and anlotinib exhibited substantial anti-tumor activity in PC(Mafei et al. 2022). Similarly, Wang et al. documented a long-term partial response and favorable tolerability in a younger PDAC patient with KRAS G12V mutation and liver metastasis who received the combination of anlotinib with PD-1 inhibitor plus chemotherapy(Wang et al. 2022). Building upon these insights, we sought to explore the potential benefits of combining tislelizumab with anlotinib in the treatment of PC, specifically focusing on patients with metastatic BRCA2 mutated PDAC. Following the administration of four treatment cycles, the patient's response to therapy was evaluated as CR, and this remarkable efficacy persisted for a duration exceeding 13 months. Table 1 provides a summary of clinical studies conducted in the context of PC involving patients with BRCA2 or BRCA1/2 mutations.

In conclusion, we presented a novel and efficacious combination therapy involving immuno- and anti-angiogenic drugs for the treatment of patients with recurrent and metastatic PDAC and BRCA2 mutations. This innovative treatment approach holds promise for diversifying the therapeutic options available to patients with recurrent and metastatic PDAC and BRCA2 mutations, particularly for individuals who either decline or are unable to tolerate conventional chemotherapy. Nonetheless, it is imperative to emphasize that rigorous and extensive clinical trials are still indispensable to substantiate its efficacy and safety, thereby advancing its adoption in clinical practice.

Author contributions

SP: Collect clinical data, accomplish and revise the paper. HH: Revise the paper and organize the paper. XZ: Pathology consultation and diagnosis. JC and XD: Organize paper. FW : Check clinical data and revise the paper. ZL and LC: Provide cases, describe the novelty and particularity of the cases, review and revise the content of the article. All authors contributed to the article and approved the submitted version.

Funding

This study was funded by the National Natural Science Foundation for Regional Fund (grant number 82360507).

Ethics approval

The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived due to the type of the study that was a case report.

Consent to participate

Written informed consent was obtained from the patient.

Consent to publish

Written informed consent was obtained from the patient for publication of this paper and any accompanying images.

Data availability statement

The original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author.

Acknowledgments

We would like to thank the patient and his family.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Park W, Chawla A, O'Reilly EM(2021) Pancreatic Cancer: A Review. Jama. 326(9):851–62
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al.(2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 71(3):209–49
Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al.(2020) Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 38(16):1763–73
Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, et al.(2023) Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 618(7963):144–50
O'Reilly EM, Lee JW, Zalupski M, Capanu M, Park J, Golan T, et al.(2020) Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. 38(13):1378–88
Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, et al.(2021) BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer. 125(10):1321–32
Wattenberg MM, Asch D, Yu S, O'Dwyer PJ, Domchek SM, Nathanson KL, et al.(2020) Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. 122(3):333–9
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al.(2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 364(19):1817–25
Reiss KA, Mick R, O'Hara MH, Teitelbaum U, Karasic TB, Schneider C, et al.(2021) Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. J Clin Oncol. 39(22):2497–505
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al.(2019) Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 381(4):317–27
Samstein RM, Krishna C, Ma X, Pei X, Lee KW, Makarov V, et al.(2021) Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. Nat Cancer. 1(12):1188–203
Terrero G, Datta J, Dennison J, Sussman DA, Lohse I, Merchant NB, et al.(2022) Ipilimumab/Nivolumab Therapy in Patients With Metastatic Pancreatic or Biliary Cancer With Homologous Recombination Deficiency Pathogenic Germline Variants. JAMA Oncol. 8(6):1–3
Huang H, Zhong P, Zhu X, Fu S, Li S, Peng S, et al.(2023) Immunotherapy combined with rh-endostatin improved clinical outcomes over immunotherapy plus chemotherapy for second-line treatment of advanced NSCLC. Front Oncol. 13:1137224
Hack SP, Zhu AX, Wang Y(2020) Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities. Front Immunol. 11:598877
Wang Y, Wang B, Xiang L, Deng J, Xu B, He P, et al.(2022) Case Report: Anlotinib combined with PD-1 inhibitor and sequential GA regimen or FOLFIRINOX Chemotherapy in treatment of KRAS G12V mutated pancreatic ductal adenocarcinoma with liver metastasis: A case and literature review. Front Immunol. 13:1016647
Mafei K, Shengyuan X, Jieqiong S(2022) Pembrolizumab enhances the anti-pancreatic cancer activity of anlotinib. Asian J Surg. 45(3):881–2
Fogelman DR, Wolff RA, Kopetz S, Javle M, Bradley C, Mok I, et al.(2011) Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer. Anticancer Res. 31(4):1417–20
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al.(2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 33(3):244–50
Sehdev A, Gbolahan O, Hancock BA, Stanley M, Shahda S, Wan J, et al.(2018) Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX. Clin Cancer Res. 24(24):6204–11
Fumet JD, Limagne E, Thibaudin M, Truntzer C, Bertaut A, Rederstorff E, et al.(2020) Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer. 20(1):748
Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, et al.(2014) Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 15(8):829–40
Lellouche L, Palmieri LJ, Dermine S, Brezault C, Chaussade S, Coriat R(2021) Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives. Ther Adv Med Oncol. 13:17588359211018539
Walsh CS(2015) Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol. 137(2):343–50
Andrei AZ, Hall A, Smith AL, Bascuñana C, Malina A, Connor A, et al.(2015) Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673. Cancer Lett. 364(1):8–16
Wang Y, Park JYP, Pacis A, Denroche RE, Jang GH, Zhang A, et al.(2020) A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer. Clin Cancer Res. 26(20):5462–76
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al.(2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 25(15):1960–6
Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al.(2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 22(8):1430–8
Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al.(2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 27(13):2231–7
Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al.(2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 28(22):3617–22
Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, et al.(2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 12(3):256–62
Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, et al.(2012) BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 23(11):2799–805
Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, et al.(2013) Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 49(12):2633–42
Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, et al.(2015) Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci. 106(7):883–90
Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, et al.(2017) CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. J Clin Oncol. 35(29):3330–7
Sun Y, Niu W, Du F, Du C, Li S, Wang J, et al.(2016) Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 9(1):105
Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, et al.(2018) Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol. 4(11):1569–75
Wu H, Huang N, Zhao C, Hu X, Da L, Huang W, et al.(2022) Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment prolongs survival in patients with unresectable or metastatic pancreatic adenocarcinoma: a retrospective cohort. Ann Transl Med. 10(6):294
Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, et al.(2018) Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 11(1):120
Yang L, Zhou X, Sun J, Lei Q, Wang Q, Pan D, et al.(2020) Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer. Cell Death Dis. 11(9):766
Zhang X, Liu Y, Zhang Z, Tan J, Zhang J, Ou H, et al.(2021) Multi-Omics Analysis of Anlotinib in Pancreatic Cancer and Development of an Anlotinib-Related Prognostic Signature. Front Cell Dev Biol. 9:649265
Timmer FEF, Geboers B, Nieuwenhuizen S, Dijkstra M, Schouten EAC, Puijk RS, et al.(2021) Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers (Basel). 13(16)
Zhang F, Wang Y, Yang F, Zhang Y, Jiang M, Zhang X(2022) The Efficacy and Safety of PD-1 Inhibitors Combined with Nab-Paclitaxel Plus Gemcitabine versus Nab-Paclitaxel Plus Gemcitabine in the First-Line Treatment of Advanced Pancreatic Cancer: A Retrospective Monocentric Study. Cancer Manag Res. 14:535–46
Shui L, Cheng K, Li X, Shui P, Zhou X, Li J, et al.(2020) Study protocol for an open-label, single-arm, phase Ib/II study of combination of toripalimab, nab-paclitaxel, and gemcitabine as the first-line treatment for patients with unresectable pancreatic ductal adenocarcinoma. BMC Cancer. 20(1):636
Liu Q, Zhao G, Zhang X, Jiang N, Zhao Z, Wang Y, et al.(2022) Nab-paclitaxel plus S-1 with or without PD-1 inhibitor in pancreatic ductal adenocarcinoma with only hepatic metastases: a retrospective cohort study. Langenbecks Arch Surg. 407(2):633–43
Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al.(2020) Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 38(1):1–10
Padrón LJ, Maurer DM, O'Hara MH, O'Reilly EM, Wolff RA, Wainberg ZA, et al.(2022) Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med. 28(6):1167–77
Feng M, Xiong G, Cao Z, Yang G, Zheng S, Song X, et al.(2017) PD-1/PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett. 407:57–65
Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al.(2010) Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 33(8):828–33
O'Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W, et al.(2019) Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 5(10):1431–8
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al.(2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357(6349):409–13
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al.(2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 380(12):1116–27
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al.(2018) Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 378(24):2288–301
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al.(2019) Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 380(12):1103–15
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al.(2020) Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 382(20):1894–905
Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, et al.(2019) Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20(5):711–8
Li SQ, Yang Y, Ye LS(2022) Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy. World J Gastroenterol. 28(42):6034–44

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Anlotinib plus Tislelizumab for Recurrent Metastatic Pancreas Ductal Adenocarcinoma with Germline BRCA2 Mutation: A Case and Literature Review

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

Introduction

Case Report

Discussion and Conclusions

Declarations

References

Additional Declarations

Status:

Version 1