The latest CT scans show progression in my lungs and liver

Understanding Your Progression on Current Therapy

Thank you for sharing this critical update. Progression in your lungs and liver while on gemcitabine/abraxane + avutometinib/defactinib is significant information that changes the clinical picture. Let me help you understand what this means and what questions to prioritize with your oncology team.

What Progression Means in Your Context

Progression means your cancer is growing despite your current treatment. This is important because:

• Your tumor markers (CEA 4.9, CA 19-9 28.7) were normal as of 4/13, but imaging shows growth—this suggests your cancer may be developing resistance to avutometinib/defactinib
• You've now had progression on three different regimens: FOLFIRINOX → RMC-6236 → current gemcitabine/abraxane + avutometinib/defactinib
• Your pMMR (proficient mismatch repair) status limits immunotherapy options, which narrows some treatment pathways
• Your elevated liver enzymes (AST 57) and low hematocrit (32.7%) suggest your liver and bone marrow are already stressed, which affects what you can tolerate next

This is a pivotal moment requiring careful strategic thinking about your next steps.

How This Affects Your Earlier Questions

About Cobimetinib

Given this progression, cobimetinib becomes more relevant as a potential option:

• Clinical reasoning: If your tumor is resistant to avutometinib (KRAS inhibitor), adding or switching to cobimetinib (MEK inhibitor) could target the same pathway from a different angle
• However: Your elevated liver enzymes and anemia suggest you may not tolerate additional chemotherapy + dual pathway inhibition well
• The SAGE Oncotest becomes even more valuable — it can test whether your resistant tumor cells respond to cobimetinib, other MEK inhibitors, or completely different drug classes

About CAR-T Cell Therapy

Your earlier question about CAR-T is still not applicable here. CAR-T is only FDA-approved for blood cancers (lymphomas, leukemias), not solid tumors like pancreatic adenocarcinoma. Progression doesn't change this—it's a biological limitation, not a treatment option.

What Your Oncology Team Is Likely Considering Now

According to NCCN Guidelines for metastatic pancreatic cancer, when patients progress on first-line therapy, oncologists typically evaluate:

1. Clinical trial eligibility — This becomes priority #1. Your progression makes you eligible for trials testing:

   • Novel KRAS inhibitors (beyond avutometinib)
   • Combination approaches with immunotherapy (though pMMR limits this)
   • Metabolic pathway inhibitors
   • Tumor microenvironment-targeting drugs

2. Switch to alternative chemotherapy — Options like:

   • 5-FU-based regimens (different from FOLFIRINOX)
   • Liposomal irinotecan + 5-FU (if not previously used)
   • Single-agent gemcitabine or nab-paclitaxel

3. Targeted therapy combinations — Potentially:

   • Different KRAS inhibitors
   • FAK inhibitors alone or in new combinations
   • MEK inhibitors like cobimetinib

4. Functional testing — Which is exactly why your SAGE Oncotest is now even more critical. With progression, this test can identify which drugs your resistant tumor actually responds to.

Critical Questions for Your Oncology Team RIGHT NOW

Given your progression, these questions should be your immediate priorities:

1. "What is driving this progression—do you think it's resistance to avutometinib, resistance to the chemotherapy, or both?" — This determines whether you switch one component or the entire regimen.

2. "Are there clinical trials I'm eligible for given my progression and pMMR status?" — Trials often have better outcomes than standard options at this stage. Ask specifically about:

   • KRAS inhibitor trials
   • Combination trials with novel agents
   • Immunotherapy combinations (even with pMMR, some trials are exploring this)

3. "Given my elevated liver enzymes and low red blood cell counts, what's my tolerance for the next regimen?" — This is crucial. Your AST of 57 and hematocrit of 32.7% mean your body is already stressed. Your doctor needs to balance efficacy with what you can actually tolerate.

4. "Should we proceed with the SAGE Oncotest as planned, and if so, which drugs should the lab prioritize testing?" — With progression, this test becomes even more valuable. Ask them to specifically test:

   • Cobimetinib and other MEK inhibitors
   • Alternative KRAS inhibitors
   • Chemotherapy combinations
   • Any drugs being considered for your next regimen

5. "What's the timeline for results, and how will we monitor response to the next treatment?" — You need to know when you'll have answers and what metrics (imaging, tumor markers, symptoms) will tell you if the new approach is working.

6. "Are there supportive care options to help with my liver function and anemia before starting the next regimen?" — Your elevated AST and low hematocrit may need management first.

What This Means for Your Treatment Strategy

Your situation now calls for:

• Rapid decision-making — Progression means time matters. You need your next treatment plan within days, not weeks
• Precision testing — The SAGE Oncotest is no longer exploratory; it's essential for guiding your next choice
• Clinical trial prioritization — At this stage, trials often offer better outcomes than standard options
• Supportive care focus — Managing your liver enzymes and anemia becomes part of the treatment plan, not just side effects

Important Context About Your Prognosis

I want to be honest with you: progression on three sequential regimens in metastatic pancreatic cancer is challenging. However:

• Your normal tumor markers (even with imaging progression) suggest slower-growing disease
• Your pMMR status, while limiting immunotherapy, means your tumor may respond to targeted approaches
• The SAGE test could identify a drug your specific tumor is sensitive to
• Clinical trials at this stage sometimes offer novel combinations not yet standard

According to the American Cancer Society and NCCN Guidelines, patients with progression on multiple regimens should prioritize:

1. Clinical trial enrollment
2. Functional drug testing (like SAGE)
3. Multidisciplinary team review (oncology, hepatology, supportive care)

---

Your Next Steps (This Week)

1. Call your oncology team immediately — Don't wait for a scheduled appointment. Progression requires urgent discussion.
2. Bring a list of these questions — Write them down so you don't forget in the conversation.
3. Ask about clinical trials — Request your team search ClinicalTrials.gov for pancreatic cancer trials you're eligible for.
4. Confirm SAGE Oncotest plan — Ask if they want to proceed and which drugs to prioritize.
5. Ask about liver/blood support — Discuss whether you need hepatology or hematology input before the next treatment.

---

This information is for educational purposes only. Always consult your healthcare team for personalized medical advice and decisions.

Your progression is serious, but it's not the end of options. Your team has tools (SAGE testing, clinical trials, alternative regimens) to explore. The key is moving quickly and strategically.