The Italian Job: Why the I-O Siena Think Tank Believes Neoadjuvant Immunotherapy Will Revolutionize Cancer Care

If the 2022 meetings from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) lit the touchpaper for explosive new advances in immuno-oncology (I-O), a subsequent meeting of international I-O experts in Tuscany blew the proverbial doors off. Since 2017, the annual I-O Siena Think Tank has brought together some of the world’s leading I-O experts to review the landscape and propose measures to translate scientific advances into clinical practice.

This year, buoyed by exciting results from high-profile trials, the Think Tank noted the potential for some game-changing breakthroughs in the fight against cancer. The main headline? Neoadjuvant immunotherapy could become the standard of care for patients with high-risk, resectable cancers—leading to less surgery and more cures, even perhaps without the need for confirmatory randomized clinical studies since the early data is so strong. These gains would represent paradigm shifts in both clinical development and the earlier treatment of cancer with curative intent. In every sense it’s an incredible prospect—a big bang moment for oncology care.

The focus on immunotherapy in the neoadjuvant setting is intensifying. In recent months, interest has been galvanized by impressive results from a number of exciting trials, with initial approvals in resectable non-small cell lung cancer (NSCLC) and for patients with locally advanced or early-stage triple-negative breast cancer (TNBC) at high risk of recurrence. This year, data from the NICHE-2 study showed treatment with neoadjuvant immunotherapy in deficient mismatch repair (dMMR) colorectal cancer (CRC) resulted in significant pathologic responses in 95% of patients. Similarly, the Phase 2 SWOG S1801 trial in patients with stage III-IV melanoma showed that neoadjuvant followed by adjuvant pembrolizumab therapy led to significantly better event-free survival compared to just adjuvant pembrolizumab. These results—presented in the same session at ESMO 2022—led the moderator to describe it as “one of the most exciting scientific sessions of any scientific congress in oncology—ever.”

The I-O Siena Think Tank involves some of the world’s foremost I-O pioneers, clinical/translational investigators, and clinical developers from across the pharmaceutical industry. Its annual meeting is organized by the world-renowned Professor Michele Maio of the Center for Immuno-Oncology, Siena, in collaboration with The Parker Institute for Cancer Immunotherapy (PICI) in San Francisco and the World Immunotherapy Council (WIC). I was lucky enough to be invited to attend the VI meeting, which followed hot on the heels of ESMO 2022. The program debated the trends and challenges shaping the future of I-O. Here are just some of the highlights.

We’re Building on the Origin Story: CTLA-4

The backbone to the future of I-O is rooted to its origin story. This was spelled out at Siena by James Allison, who shared the 2018 Nobel Prize in Physiology or Medicine for the discovery of cancer therapy by inhibition of negative immune regulation—immune checkpoint inhibitors—and the development of the first anti-CTLA-4 immunotherapy, ipilimumab. His “Nobel lecture” in Siena told the CTLA-4 story, outlining its initial development, evolving role, and advances in combination for the treatment of a wide range of advanced cancers.

The use of ipilimumab together with a PD(L)-1 inhibitor continues to surprise today, now in the neoadjuvant setting. As referenced earlier, this was most recently seen with the NICHE-2 data presented at ESMO 2022. The data stood out, partly because the pathological complete response (pCR) waterfall plot was coined by some as a “Niagara Falls plot,” but also due to its implications for patients with dMMR CRC. This could represent around 15% of diagnosed CRC cases. In NICHE-2, patients with dMMR non-metastatic CRC received one dose of ipilimumab and two doses of nivolumab. Since the patients were scheduled for surgery within six weeks after the three doses of I-O, pathological assessment of the tissue showed that almost all (99%) patients demonstrated a significant (95%) or complete (67%) pathological response meaning that the tumor was necrotic and entirely or significantly reduced in size.

The use of other multiple combinations, some building on that backbone, is a trend we can expect to see more of in the future. More on that later.

Advancements of Neoadjuvant I-O in Lung Cancer, Breast Cancer, and High-risk Melanoma

The trend towards neoadjuvant immunotherapy is already gathering pace. 2022 saw the approval of the PD-1 inhibitor pembrolizumab, in combination with chemotherapy, for patients with resectable NSCLC. In addition, anti-PD-1 therapy in combination with chemotherapy as neoadjuvant treatment—and then continued as monotherapy adjuvant therapy after surgery—was also approved this year for patients with locally advanced or early-stage TNBC at high risk of recurrence.

However, there is still debate regarding neoadjuvant and adjuvant immunotherapy in resectable tumors—and a study presented at ESMO in high-risk melanoma confirmed that “it’s not just what you give, it’s when you give it.” The S1801 study by the SWOG Cancer Research Network investigated outcomes with three doses of pembrolizumab as neoadjuvant therapy, with another 15 adjuvant doses post-surgery versus 18 doses given only in the post-surgical adjuvant setting. The results, referenced earlier, showed that event-free survival was significantly longer in the neoadjuvant arm when compared to the adjuvant therapy arm (HR 0.58), representing a 42% lower event rate. The study investigators summarized that: “based on the findings from S1801, patients with high-risk melanoma should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact.”

This, as explained in Siena, potentially represents a whole new standard of care. Typically, melanoma patients with palpable lymph nodes would have those removed before being given therapy to prevent recurrence. S1801 shows that neoadjuvant immunotherapy—three injections prior to surgery—primes the immune system to recognize the tumor(s). When those tumors are finally removed, the immune system still recognizes any micro metastases for a long time afterwards, protecting the patient and reducing the recurrence rate to almost zero. It’s outstanding data with potential application across other cancer types.

Future of Neoadjuvant I-O—Less Need for Surgery, More Cures!

Lex Eggermont, Professor of Clinical and Translational Immunotherapy at Utrecht University, pointed to the Netherlands’ successes with screening and biomarker testing for cancers such as CRC as an example of I-O driving new standards of care. In the Netherlands, doctors are now being advised to refer patients to centers which can test patients for dMMR when they’re diagnosed with non-metastatic CRC to identify those eligible for neoadjuvant immunotherapy. Early diagnosis and testing may remove the need for surgery and replace it with follow-up endoscopy and MRI. Eggermont believes that neoadjuvant immunotherapy for other cancers—such as bladder, lung, breast, and esophageal—can also inspire similar gains in standards of care.

Continuing Research into I-O Combinations for Non-responders/Resistant Patients

Developing new combinations to improve response in patients with metastatic and hard-to-treat cancers is receiving a huge focus in cases where we’re not always seeing the benefit with the immune checkpoint inhibitors that we see in lung, renal, melanoma, and other cancers. Certain tumors—such as pancreatic, prostate, and glioblastoma—aren’t as responsive and the checkpoints fail to stir the immune system. This confirms the importance of the tumor microenvironment in shaping the response to immunotherapy. Multiple combinations are becoming the next line of approach in advanced disease.

Pharma companies are investing heavily in the prospect. Currently, thousands of ongoing trials are looking at new combinations where other immune-active drugs are being added to backbone checkpoint inhibitors to test response. The challenge is balancing toxicity, because adding too much can make the combination more toxic than the potential benefit. Overcoming this requires understanding the biology of tumors—potentially through smaller studies in which patients are biopsied and the tissue examined to determine what’s happening. With too many large studies failing—at great cost—we’re likely to see a shift to smaller studies of new combinations as companies look for better immune responses in advanced cancers.

What’s Next?

So, what does all this mean for pharma? Clearly, we have some way to go before neoadjuvant I-O establishes itself as a more accessible standard of care. However, as pharma continues to invest billions in I-O development, an urgent need is developing for medical communications to raise awareness of the advances already being made in clinical practice. That’s the rallying call to pharma companies and their agency partners. If we can spread the word to HCPs—just like they’re doing in the Netherlands—we can start to reimagine treatment pathways and transform patient outcomes. What’s more, if we can share the message with patient populations, we can change the conversation and give renewed hope to people burdened by—or in fear of—a cancer diagnosis to improve screening and earlier treatment.

  • Michael Smith

    Michael Smith is Group Scientific Director at VMLY&R Health (Milan-Paris-Zurich-Cambridge MA) with over 30 years' experience in healthcare communications and has helped build a large team of specialist medical writers working primarily across immunology, oncology, neurology and rare diseases.

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