Combination of Osimertinib and Olaparib Therapy to Treat Non-Small Cell Lung Cancer and High-Grade Serous Ovarian Carcinoma: A Case Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Lin and colleagues presented case report that  a 75-year-old female with EGFR-mutatation associated late stage lung cancer and advanced BRCA2-mutated ovarian cancer with specific treatment regimen. It is a unique case with dual tumor associated with resistance to EGFR-TKI  and further combination treatment with osimertinib and olaparib and it has been well discussed and written, this makes this manuscript for probable publication.

Author Response

Thank you very much for taking the time to review this manuscript. We appreciate your comments.

Reviewer 2 Report

Comments and Suggestions for Authors

Manuscript proposed by Lin et al., is coinse and well written, I have only one minor suggestion for the Authors.

1. It would be nice to add some information about in vitro or in vivo data about combination of osimertinim and olaparib therapy, are these data avaible for lung cancer or high grade serous ovarian carcinoma?

Comments on the Quality of English Language

Only minor spelling language edditing is suggested.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the response below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

Comment 1: It would be nice to add some information about in vitro or in vivo data about combination of osimertinim and olaparib therapy, are these data avaible for lung cancer or high grade serous ovarian carcinoma?

Response 1: Thank you for the comment. To our knowledge and literature search, there is no in vitro or in vivo data for this drug combination. 

Added "There are no in vitro or in vivo data available on osimertinib and olaparib interactions."

In terms of the English editing, we will continue to look for spelling/grammar errors but so far we have not found any major ones that we need to adjust.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for submitting this interesting and informative manuscript to Current Oncology. I was pleased to receive it as a reviewer.

While your case report provides valuable insights into an important clinical topic, there are some areas that could be refined to further augment the quality and impact of the work. Here are some respectful suggestions that could potentially improve the paper if you choose to implement them:

Introduction

·         The background provides appropriate context, though more details on incidence and prognosis of dual lung-ovarian primary malignancies could better position the novelty.

·         Consider briefly explaining the standard management for each individual cancer type to better showcase how this case deviates from usual protocols.

Case Presentation

·         A few more details on patient symptoms and quality of life over time may enrich this section. This could emphasize the clinical decision-making balancing disease control versus side effects.

Discussion

·         Commenting on options besides EGFR and PARP inhibition available for managing resistance can underscore why alternating targeted therapies was reasonable in this scenario.

·         Addressing cost/coverage considerations and feasibility of implementing this regimen more widely could be relevant to discuss, especially for settings with limited resources.

Conclusions

·         A more nuanced and balanced perspective commenting on both the successes and limitations of the tailored regimen could strengthen the concluding remarks.

Overall, these suggestions aim to enhance the manuscript's quality and impact for clinicians and researchers. I believe that implementing the above suggestions would make your important work even stronger.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comment 1: Introduction

• The background provides appropriate context, though more details on incidence and prognosis of dual lung-ovarian primary malignancies could better position the novelty.
• Consider briefly explaining the standard management for each individual cancer type to better showcase how this case deviates from usual protocols.

Response 1: Thank you for your wonderful suggestions. We have included details on the incidence and prognosis of dual LC and OC. In terms of standard treatment, we believe that this is mentioned in the second and third paragraph. LC mainstay treatment is surgery, chemo, radiation; and can be guided by molecular driver mutations for specific targeted therapy. BRCA mutated OC mainstay treatment is platinum-based chemo, followed by PARPi. We have added cytoreductive surgery as a standard treatment for OC. 

Added: "and so far, no literature data are available on the incidence of this double primary. In advanced stages, prognosis is poor for both malignancies [2]."

Added: "[Treatments for BRCA-mutated ovarian cancer include first line platinum-based chemotherapy] and cytoreductive surgery"

Comment 2: Case Presentation

• A few more details on patient symptoms and quality of life over time may enrich this section. This could emphasize the clinical decision-making balancing disease control versus side effects.

Response 2:

Added "The patient reported minimal side effects from osimertinib aside from occasional nausea well controlled with antiemetics, and her quality of life was well maintained."

Added "These included constant nausea, dysgeusia, fatigue, and lack of appetite, which significantly reduced her quality of life."

Comment 3: Discussion

• Commenting on options besides EGFR and PARP inhibition available for managing resistance can underscore why alternating targeted therapies was reasonable in this scenario.
• Addressing cost/coverage considerations and feasibility of implementing this regimen more widely could be relevant to discuss, especially for settings with limited resources.

Response 3: 

Added: "Given the lung cancer comorbidity, surgical cytoreduction was not recommended for her ovarian cancer. Response rates for cytotoxic chemotherapy are lower, and toxicity profiles usually worse, than targeted therapies in both lung and ovarian cancer. The patient did receive carboplatin and paclitaxel at one point, which would cover both diseases, but has lower brain penetration than anti-EGFR treatment, which was important in this case, which is why targeted therapy was preferred in the longer term."

Added: "The feasibility of maintaining control, for some time, with reasonable toxicity, of two cancers with an alternating schedule that effectively reduced the dose intensity of either drug, raises possibilities for efficient use of targeted drugs in resource-constrained contexts."

Comment 4: Conclusions

• A more nuanced and balanced perspective commenting on both the successes and limitations of the tailored regimen could strengthen the concluding remarks.

Response 4: We have added minor details to both success and limitation of this regimen, highlighted in the Conclusions.

Added: "[This case report demonstrated the potential of osimertinib and olaparib combination therapy to treat simultaneous NSCLC and ovarian serous carcinoma], which can reduce risks of progression and reduce patient anxiety."

Added: "These side effects may significantly impact functioning, which can undermine the patients’ goals if not explored."

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

This case report by Lin et al is very interesting indeed. As noted in the introduction, there is a rather low incidence of multiple primary cancers in a patient. What makes this case intriguing is that both the cancers had metastatic growth to brain (NSCLC) and Liver (Ovarian cancer). Since the NSCLC was diagnosed first, following a left temporal craniotomy, the radiation therapy and subsequent first and second generation TKIs stabilized initial disease progression. This was a reasonable treatment strategy. Due to hypersensitivity to second generation TKI, T790M mutation was investigated for use of osimertinib. This investigation revealed presence of ovarian cancer that was treated with chemotherapy (carboplatin plus paclitaxel) to control ovarian cancer. Following chemotherapy, Osimertinib was prioritized to treat stage four NSCLC. Later on, new progression of ovarian cancer occurred and additional chemotherapy cycles and maintenance dose of PARP inhibitor (Olaparib) were used. As the ovarian cancer continued to metastasize, combination use of Osimertinib and Olaparib proved toxic with reduced efficacy. Although combination of targeted drugs have been tried in patient with single malignancy, the use of two targeted drugs in a patient with two cancers appears a novel case. As this reviewer is a basic scientist with research interests in drug development for lung and breast cancers, the use of PARP inhibitor likely also impacted NSCLC in this patient as cancers in general are dependent on DNA repair mechanisms due to elevated demand of rapid cell proliferation and division. Olaparib likely contributed to also controlling NSCLC during the periods when the drugs (Osimertinib abd olaparib) were switched. Although the patient is currently on Osimertinib, it is possible that liver metastasis of ovarian cancer will continue and at some point, necessitate Olaparib use again. Overall, although this case has presented a difficult and challenging clinical situation that has been complicated with progression and metastatic disease, the rationale for use of the targeted drugs and the strategies was appropriate that did result in significantly higher PFS and OS. 

Author Response

Thank you very much for taking the time to review this manuscript. We appreciate your comments.